Compounds for treatment of cancer

ABSTRACT

The present invention relates to novel compounds having anti-cancer activity, methods of making these compounds, and their use for treating cancer and drug-resistant tumors, e.g. melanoma, metastatic melanoma, drug resistant melanoma, prostate cancer and drug resistant prostate cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation-In-Part Application of U.S. patentapplication Ser. No. 12/485,881, filed Jun. 16, 2009, which claimspriority from U.S. Provisional Application Ser. No. 61/061,875, filedJun. 16, 2008; this Application claims priority from U.S. ProvisionalApplication Ser. No. 61/376,675, filed Aug. 24, 2010; U.S. ProvisionalApplication Ser. No. 61/315,790, filed Mar. 19, 2010; and from U.S.Provisional Application Ser. No. 61/309,360, filed Mar. 1, 2010; all ofwhich are hereby incorporated by reference in their entirety.

GOVERNMENT INTEREST STATEMENT

This invention was made in whole or in part with government supportunder Grant Number 1R15CA125623-01A2, awarded by the (NationalInstitutes of Health). The government has certain rights in theinvention.

FIELD OF THE INVENTION

The present invention relates to novel compounds having anti-canceractivity, methods of making these compounds, and their use for treatingcancer, treating drug-resistant tumors, drug-resistant cancer,metastatic cancer, metastatic melanoma, drug resistant melanoma,prostate cancer and drug resistant prostate cancer.

BACKGROUND OF THE INVENTION

Cancer is the second most common cause of death in the United States,exceeded only by heart disease. In the United States, cancer accountsfor 1 of every 4 deaths. The 5-year relative survival rate for allcancer patients diagnosed in 1996-2003 is 66%, up from 50% in 1975-1977(Cancer Facts & Figures American Cancer Society: Atlanta, Ga. (2008)).This improvement in survival reflects progress in diagnosing at anearlier stage and improvements in treatment. Discovering highlyeffective anticancer agents with low toxicity is a primary goal ofcancer research.

Microtubules are cytoskeletal filaments consisting of αβ-tubulinheterodimers and are involved in a wide range of cellular functions,including shape maintenance, vesicle transport, cell motility, anddivision. Tubulin is the major structural component of the microtubulesand a well verified target for a variety of highly successfulanti-cancer drugs. Compounds that are able to interfere withmicrotubule-tubulin equilibrium in cells are effective in the treatmentof cancers. Anticancer drugs like taxol and vinblastine that are able tointerfere with microtubule-tubulin equilibrium in cells are extensivelyused in cancer chemotherapy. There are three major classes ofantimitotic agents. Microtubule-stabilizing agents, which bind to fullyformed microtubules and prevent the depolymerization of tubulinsubunits, are represented by taxanes and epothilones. The other twoclasses of agents are microtubule-destabilizing agents, which bind totubulin dimers and inhibit their polymerization into microtubules. Vinaalkaloids such as vinblastine bind to the vinca site and represent oneof these classes. Colchicine and colchicine-site binders interact at adistinct site on tubulin and define the third class of antimitoticagents.

Both the taxanes and vinca alkaloids are widely used to treat humancancers, while no colchicine-site binders are currently approved forcancer chemotherapy yet. However, colchicine binding agents likecombretastatin A-4 (CA-4) and ABT-751 (FIG. 19), are now under clinicalinvestigation as potential new chemotherapeutic agents (Luo, Y.; Hradil,V. P.; Frost, D. J.; Rosenberg, S. H.; Gordon, G. B.; Morgan, S. J.;Gagne, G. D.; Cox, B. F.; Tahir, S. K.; Fox, G. B., ABT-751, “a noveltubulin-binding agent, decreases tumor perfusion and disrupts tumorvasculature”. Anticancer Drugs 2009, 20, (6), 483-92.; Mauer, A. M.;Cohen, E. E.; Ma, P. C.; Kozloff, M. F.; Schwartzberg, L.; Coates, A.I.; Qian, J.; Hagey, A. E.; Gordon, G. B., “A phase II study of ABT-751in patients with advanced non-small cell lung cancer”. J Thorac Oncol2008, 3, (6), 631-6.; Rustin, G. J.; Shreeves, G.; Nathan, P. D.; Gaya,A.; Ganesan, T. S.; Wang, D.; Boxall, J.; Poupard, L.; Chaplin, D. J.;Stratford, M. R.; Balkissoon, J.; Zweifel, M., “A Phase 1b trial of CA4P(combretastatin A-4 phosphate), carboplatin, and paclitaxel in patientswith advanced cancer”. Br J Cancer 2010, 102, (9), 1355-60.).

Unfortunately, microtubule-interacting anticancer drugs in clinical useshare two major problems, resistance and neurotoxicity. A commonmechanism of multidrug resistance (MDR), namely ATP binding cassette(ABC) transporter protein-mediated drug efflux, limits their efficacy(Green, H.; Rosenberg, P.; Soderkvist, P.; Horvath, G.; Peterson, C.,“beta-Tubulin mutations in ovarian cancer using single strandconformation analysis-risk of false positive results from paraffinembedded tissues”. Cancer letters 2006, 236, (1), 148-54.; Wang, Y.;Cabral, F., “Paclitaxel resistance in cells with reduced beta-tubulin”.Biochimica et Biophysica Acta, Molecular Cell Research 2005, 1744, (2),245-255.; Leslie, E. M.; Deeley, R. G.; Cole, S. P. C., “Multidrugresistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP(ABCG2) in tissue defense”. Toxicology and Applied Pharmacology 2005,204, (3), 216-237.).

P-glycoproteins (P-gp, encoded by the MDR1 gene) are important membersof the ABC superfamily. P-gp prevents the intracellular accumulation ofmany cancer drugs by increasing their efflux out of cancer cells, aswell as contributing to hepatic, renal, or intestinal clearancepathways. Attempts to co-administer P-gp modulators or inhibitors toincrease cellular availability by blocking the actions of P-gp have metwith limited success (Gottesman, M. M.; Pastan, I., “The multidrugtransporter, a double-edged sword”. J Biol Chem 1988, 263, (25),12163-6.; Fisher, G. A.; Sikic, B. I., “Clinical studies with modulatorsof multidrug resistance”. Hematology/oncology clinics of North America1995, 9, (2), 363-82).

The other major problem with taxanes, as with many biologically activenatural products, is its lipophilicity and lack of solubility in aqueoussystems. This leads to the use of emulsifiers like Cremophor EL andTween 80 in clinical preparations. A number of biologic effects relatedto these drug formulation vehicles have been described, including acutehypersensitivity reactions and peripheral neuropathies (Hennenfent, K.L.; Govindan, R., “Novel formulations of taxanes: a review. Old wine ina new bottle?” Ann Oncol 2006, 17, (5), 735-49.; ten Tije, A. J.;Verweij, J.; Loos, W. J.; Sparreboom, A., “Pharmacological effects offormulation vehicles: implications for cancer chemotherapy”. ClinPharmacokinet 2003, 42, (7), 665-85.).

Compared to compounds binding the paclitaxel- or vinca alkaloid bindingsite, colchicine-binding agents usually exhibit relatively simplestructures. Thus providing a better opportunity for oral bioavailabilityvia structural optimization to improve solubility and pharmacokinetic(PK) parameters. In addition, many of these drugs appear to circumventP-gp-mediated MDR. Therefore, these novel colchicine binding sitetargeted compounds hold great promise as therapeutic agents,particularly since they have improved aqueous solubility and overcomeP-gp mediated MDR.

Prostate cancer is one of the most frequently diagnosed noncutaneouscancers among men in the US and is the second most common cause ofcancer deaths with over 180,000 new cases and almost 29,000 deathsexpected this year. Patients with advanced prostate cancer undergoandrogen deprivation therapy (ADT), typically either by luteinizinghormone releasing hormone (LHRH) agonists or by bilateral orchidectomy.Androgen deprivation therapy not only reduces testosterone, but estrogenlevels are also lower since estrogen is derived from the aromatizationof testosterone, which levels are depleted by ADT. Androgen deprivationtherapy-induced estrogen deficiency causes significant side effectswhich include hot flushes, gynecomastia and mastalgia, bone loss,decreases in bone quality and strength, osteoporosis andlife-threatening fractures, adverse lipid changes and highercardiovascular disease and myocardial infarction, and depression andother mood changes. It is believed that many of the estrogen deficiencyside effects of ADT are mediated by ERα.

Leuprolide acetate (Lupron®) is a synthetic nonapeptide analog ofnaturally occurring gonadotropin-releasing hormone (GnRH or LH-RH).Leuprolide acetate is an LH-RH superagonist that eventually suppressesLH secretion by the pituitary. Leuprolide acetate acts as a potentinhibitor of gonadotropin secretion, resulting in suppression of ovarianand testicular steroidogenesis. In humans, administration of leuprolideacetate results in an initial increase in circulating levels ofluteinizing hormone (LH) and follicle stimulating hormone (FSH), leadingto a transient increase in levels of the gonadal steroids (testosteroneand dihydrotestosterone in males, and estrone and estradiol inpremenopausal females). However, continuous administration of leuprolideacetate results in decreased levels of LH and FSH. In males,testosterone is reduced to castrate levels (below 50 ng/dL). Inpremenopausal females, estrogens are reduced to postmenopausal levels.Testosterone is a known stimulus for cancerous cells of the prostate.Suppressing testosterone secretion or inhibiting the actions oftestosterone is thus a necessary component of prostate cancer therapy.Leuprolide acetate can be used for LH suppression, which is thereduction and lowering of serum testosterone to castrate levels to treatprostate cancer.

Malignant melanoma is the most dangerous form of skin cancer, accountingfor about 75% of skin cancer deaths. The incidence of melanoma is risingsteadily in Western populations. The number of cases has doubled in thepast 20 years. Around 160,000 new cases of melanoma are diagnosedworldwide each year, and it is more frequent in males and Caucasians.According to a WHO Report, about 48,000 melanoma-related deaths occurworldwide per year.

Currently there is no effective way to treat metastatic melanoma. It ishighly resistant to current chemotherapy, radiotherapy, andimmunotherapy. Metastatic melanoma has a very poor prognosis, with amedian survival rate of 6 months and a 5-year survival rate of less than5%. In the past 30 years, dacarbazine (DTIC) is the only FDA-approveddrug for metastatic melanoma. However, it provides only less than 5% ofcomplete remission in patients. In recent years, great efforts have beenattempted in fighting metastatic melanoma. Neither combinations of DTICwith other chemotherapy drugs (e.g., cisplatin, vinblastine, andcarmustine) nor adding interferon-a2b to DTIC have shown a survivaladvantage over DTIC treatment alone. Most recently, clinical trials withantibodies and vaccines to treat metastatic melanoma also failed todemonstrate satisfactory efficacy.

Melanoma cells have low levels of spontaneous apoptosis in vivo comparedwith other tumor cell types, and they are relatively resistant todrug-induced apoptosis in vitro. The natural role of melanocytes is toprotect inner organs from UV light, a potent DNA damaging agent.Therefore, it is not surprising that melanoma cells may have special DNAdamage repair systems and enhanced survival properties. Moreover, recentstudies showed that, during melanoma progression, it acquired complexgenetic alterations that led to hyperactivation of efflux pumps,detoxification enzymes, and a multifactoral alteration of survival andapoptotic pathways. All these have been proposed to mediate themultidrug-resistant (MDR) phenotype of melanoma. With the rapidly risingincidence of this disease and the high resistance to current therapeuticagents, developing more effective drugs for advanced melanoma and othercancer types that can effectively circumvent MDR will providesignificant benefits to cancer patients.

SUMMARY OF THE INVENTION

In one embodiment, this invention is directed to a compound representedby the structure of formula (Ia):

whereinA is substituted or unsubstituted single-, fused- or multiple-ring, arylor (hetero)cyclic ring systems; substituted or unsubstituted, saturatedor unsaturated N-heterocycles; substituted or unsubstituted, saturatedor unsaturated S-heterocycles; substituted or unsubstituted, saturatedor unsaturated O-heterocycles; substituted or unsubstituted, saturatedor unsaturated cyclic hydrocarbons; or substituted or unsubstituted,saturated or unsaturated mixed heterocycles;

B is

R₁, R₂ and R₃ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl,Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;R₁₀ and R₁₁ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br,I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;X is a bond, NH, C₁ to C₅ hydrocarbon, O, or S;Y is a bond, —C═O, —C═S, —C═N—NH₂, —C═N—OH, —CH—OH, —C═CH—CN; —C═N—CN,—CH═CH—, —C═C(CH₃)₂, —C═N—OMe, —(C═O)—NH, —NH—(C═O), —(C═O)—O, —O—(C═O),—(CH₂)₁₋₅—(C═O), (C═O)—(CH₂)₁₋₅, —(SO₂)—NH—, —NH—(SO₂)—, SO₂, SO or S;wherein said A and B rings are optionally substituted by 1-5substituents which are independently O-alkyl, O-haloalkyl, F, Cl, Br, I,haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O—alkyl, C(O)H, —C(O)NH₂ or NO₂;i is an integer between 0-5;l is an integer between 1-2;m is an integer between 1-3; andwherein if B is a benzene ring, a thiophene ring, a furane ring or anindole ring then X is not a bond or CH₂ and A is not indole;if B is indole then X is not O; andif B ring is a thiazole then X is not a bond;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, this invention is directed to a compound representedby the structure of formula II:

wherein

B is

R₁, R₂, R₃, R₄, R₅ and R₆ are independently hydrogen, O-alkyl,O-haloalkyl, F, Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl,—(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph,—NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;R₁₀ and R₁₁ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br,I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;X is a bond, NH, C₁ to C₅ hydrocarbon, O, or S;Y is a bond, —C═O, —C═S, —C═N—NH₂, —C═N—OH, —CH—OH, —C═CH—CN,—C═N—CN, —CH═CH—, C═CH(CH₃)₂, —C═N—OMe, —(C═O)—NH, —NH—(C═O), —(C═O)—O,—O—(C═O), —(CH₂)₁₋₅—(C═O), (C═O)—(CH₂)₁₋₅, —(SO₂)—NH—, —NH—(SO₂)—, SO₂,SO or S;i is an integer between 0-5;l is an integer between 1-2;n is an integer between 1-3; andm is an integer between 1-3;wherein if B is indole then X is not O; andif B ring is a thiazole then X is not a bond;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, this invention is directed to a compound representedby the structure of formula (V):

wherein

B is

R₄, R₅ and R₆ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl,Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;R₁₀ and R₁₁ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br,I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branched alkyl, haloalkyl,alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph,C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;i is an integer between 0-5;l is an integer between 1-2; andn is an integer between 1-3;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, this invention is directed to a compound representedby the structure of formula (XI):

whereinX is a bond, NH or S;

Q is O, NH or S;

A is substituted or unsubstituted single-, fused- or multiple-ring, arylor (hetero)cyclic ring systems; substituted or unsubstituted, saturatedor unsaturated N-heterocycles; substituted or unsubstituted, saturatedor unsaturated S-heterocycles; substituted or unsubstituted, saturatedor unsaturated O-heterocycles; substituted or unsubstituted, saturatedor unsaturated cyclic hydrocarbons; or substituted or unsubstituted,saturated or unsaturated mixed heterocycles; wherein said A ring isoptionally substituted by 1-5 substituents which are independentlyO-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂,hydroxyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃,C₁-C₅ linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl,—OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ orNO₂; andi is an integer between 0-5;wherein if Q is S then X is not a bond;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, this invention is directed to a compound representedby the structure of formula (VIII):

whereinR₄, R₅ and R₆ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl,Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;

Q is S, O or NH;

i is an integer between 0-5; andn is an integer between 1-3;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, this invention is directed to a compound representedby the structure of formula [XI(b)]:

wherein R₄ and R₅ are independently hydrogen, O-alkyl, O-haloalkyl, F,Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;i is an integer from 0-5; andn is an integer between 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, this invention is directed to a compound representedby the structure of formula [XI(c)]:

wherein R₄ and R₅ are independently hydrogen, O-alkyl, O-haloalkyl, F,Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;i is an integer from 0-5; andn is an integer between 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, this invention is directed to a compound representedby the structure of formula [XI(e)]:

wherein R₄ and R₅ are independently hydrogen, O-alkyl, O-haloalkyl, F,Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;i is an integer from 0-5; andn is an integer between 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, this invention is directed to a compound representedby the structure of formula (XVI):

wherein R₄ and R₅ are independently H, O-alkyl, I, Br, Cl, F, alkyl,haloalkyl, aminoalkyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂,—(CH₂)_(i)N(CH₃)₂, OCH₂Ph, OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkylor C(O)H;

R₃ is I, Br, Cl, F;

i is an integer between 0-5; andn is an integer between 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, this invention is directed to a compound representedby the structure of formula IX:

R₄ and R₅ are independently selected from hydrogen, O-alkyl,O-haloalkyl, F, Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl,—(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph,—NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —(O)NH₂ or NO₂;A′ is substituted or unsubstituted single-, fused- or multiple-ring,aryl or (hetero)cyclic ring systems, including saturated and unsaturatedN-heterocycles, saturated and unsaturated S-heterocycles, and saturatedand unsaturated O-heterocycles, saturated or unsaturated cyclichydrocarbons, saturated or unsaturated mixed heterocycles or aliphaticstraight- or branched-chain C₁ to C₃₀ hydrocarbons; wherein said A ringis optionally substituted by 1-5 same or different substituentscomprising O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF₃, CN,—CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂,—(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branched alkyl, haloalkyl,alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph,C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;i is an integer between 0-5; andn is an integer between 1-3;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, this invention is directed to a compound representedby the structure of compound (55):

In one embodiment, this invention is directed to a compound representedby the structure of compound (17ya):

In one embodiment, this invention is directed to a compound representedby the structure of compound 12da:

In one embodiment, this invention is directed to a compound representedby the structure of compound (12fa):

In one embodiment, this invention is directed to a compound representedby the structure of compound (12cb):

In one embodiment, this invention is directed to a compound representedby the structure of compound (12fb):

In one embodiment, this invention is directed to a compound representedby the structure of compound (6b):

In one embodiment, this invention is directed to a pharmaceuticalcomposition comprising a compound of this invention and apharmaceutically acceptable carrier.

In one embodiment this invention is directed to a method of (a)treating, suppressing, reducing the severity, reducing the risk, orinhibiting cancer; (b) treating a drug resistant tumor or tumors; and(c) destroying a cancerous cell comprising administering a compound ofthis invention. In another embodiment the cancer is selected from thegroup consisting of prostate cancer, breast cancer, ovarian cancer, skincancer, melanoma, lung cancer, colon cancer, leukemia, renal cancer, CNScancer, and combinations thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

The subject matter regarded as the invention is particularly pointed outand distinctly claimed in the concluding portion of the specification.The invention, however, both as to organization and method of operation,together with objects, features, and advantages thereof, may best beunderstood by reference to the following detailed description when readwith the accompanying drawings in which:

FIG. 1 depicts the synthesis of the diverse B-ring template: oxazole.Reagents and conditions: (a) MeOH, CH₃COCl, 83%; (b) Benzimidic acidethyl ester, CH₂Cl₂, Et₃N, 96%; (c) LiOH, MeOH, H₂O, 65%; (d) EDCI,HOBt, NMM, CH₃OCH₃NH.HCl, 61%; (e) 3,4,5-trimethoxyphenylmagnesiumbromide, THF, 48%-71%; (f) CBrCl₃, DBU, CH₂Cl₂, 56%.

FIG. 2 depicts the synthesis of the diverse B-ring templates. Reagentsand conditions: (a) EDCI, HOBt, NMM, CH₃OCH₃NH.HCl, CH₂Cl₂, 51-95%; (b)3,4,5-trimethoxyphenyl-magnesium bromide, THF, 48-78%; (c) LAH, −78° C.,UV, 85%; (d) Dess-Martin reagent, CH₂Cl₂, 81%; (e) EDCI, HOBt, NMM,3,4,5-trimethoxybenzoic acid, CH₂Cl₂, 58%.

FIG. 3 depicts the synthetic scheme of compounds of this invention.Reagents and conditions: (a) MeOH/pH=6.4 phosphate buffer, RT; (b) EDCI,HOBt, NMM, HNCH₃OCH₃; (c) CBrCl₃, DBU, CH₂Cl₂; (d)3,4,5-trimethoxyphenylmagnesium bromide, THF; (e) isopropyltriphenylphosphonium iodide, n-BuLi, THF; (f) LAH, THF; (g) For 2e-cisand 2e-trans, NH₂OH.HCl, C₂H₅OH, H₂O, NaOH; For 2g and 2h, NH₂OMe.HCl,pyridine; (h) TsCl, NaH, basic Al₂O₃; (i) NH₂NH.xH₂O, CH₂Cl₂, t-BuOH;(j) diethyl cyanomethylphosphonate, n-BuLi, THF; (k)bis-trimethylsilylcarbodiimide, TiCl₄, CH₂Cl₂; (1) EDCI, HOBt, Et₃N,3,4,5-trimethoxyaniline, CH₂Cl₂.

FIG. 4 depicts the synthetic scheme of compounds of this invention.Reagents and conditions: (a) bromine, EtOH; (b) benzothioamide, EtOH,reflux; (c) EDCI, HOBt, NMM, HNCH₃OCH₃, CH₂Cl₂; (d) CBrCl₃, DBU, CH₂Cl₂;(e) LAH, THF; (f) 5-(bromomethyl)-1,2,3-trimethoxybenzene, Ph₃P, THF;(g) n-BuLi, THF; (h) (1) HCl, H₂O; (2) NaNO₂, H₂O, 0° C.; (i) ethylpotassium xanthate; (j) KOH/EtOH; (k) H₂O, HCl; (1)5-iodo-1,2,3-trimethoxybenzene, CuI, t-BuONa; (m) 2 equiv or 1 equivm-CPBA, CH₂Cl₂; (n) 3,4,5-trimethoxyaniline, NEt₃, DMF.

FIG. 5 depicts the synthetic scheme of compounds of this invention.Reagents and conditions: (a) L-cysteine, EtOH, 65° C.; (b) EDCI, HOBt,NMM, HNCH₃OCH₃, CH₂Cl₂; (c) TBDMSCl, imidazole, THF; (d)3,4,5-trimethoxyphenylbromide, BuLi, THF; (e) TBAF, THF; (f) SOCl₂,Et₂O; (g) NH₃, MeOH; (h) POCl₃; (i) PhSO₂Cl, Bu₄NHSO₄, toluene, 50%NaOH; (j) 1 N NaOH, EtOH, reflux; (k) Boc₂O, 1 N NaOH, 1,4-dioxane; (l)CBrCl₃, DBU, CH₂Cl₂; (m) 4 N HCl in 1,4-dioxane; (n) NaH, DMF, MeI; (o)HCHO, NaBH₃CN, Et₃N.

FIG. 6 depicts the synthetic scheme of compounds of this invention.Reagents and conditions: (a) EtOH, 65° C.; (b) NaOH, C₂H₅OH, refluxing;(c) EDCI, HOBt, NMM, HNCH₃OCH₃, CH₂Cl₂; (d)3,4,5-trimethoxyphenylbromide, BuLi, THF; (e) 2 N HCl in 1,4-dioxane.

FIG. 7 depicts a synthetic scheme for the preparation ofAryl-Benzoyl-Imidazole (ABI) compounds of this invention. Reagents andconditions: (a) t-BuOH, I₂, ethylenediamine, K₂CO₃, reflux; (b) PhI(OAc)₂, K₂CO₃, DMSO; (c) DBU, CBrCl₃, DMF; (d) NaH, PhSO₂Cl, THF, 0°C.-RT; (e) t-BuLi, substituted benzoyl chloride, THF, −78° C.; (f)Bu₄NF, THF, RT.

FIG. 8 depicts a synthetic scheme for the preparation ofAryl-Benzoyl-Imidazole (ABI) compounds of this invention. Reagents andconditions: (a) NH₄OH, oxalaldehyde, ethanol, RT; (b) NaH, PhSO₂Cl, THF,0° C.-RT; (c) t-BuLi, substituted benzoyl chloride, THF, −78° C.; (d)Bu₄NF, THF, RT; (e) BBr₃, CH₂Cl₂; (f) c-HCl, AcOH, reflux.

FIG. 9 depicts a synthetic scheme for the preparation ofAryl-Benzoyl-Imidazole (ABI) compounds of this invention. Reagents andconditions: (a) NaH, substituted benzoyl chloride, THF.

FIG. 10 depicts the synthetic scheme of compounds 12dc, 12fc, 12daa,12dab, 12cba. (a) AlCl₃, THF, reflux; (b) NaH, CH₃I for 12dab and 12cbaand BnBr for 12daa, THF, reflux.

FIG. 11 depicts the synthetic scheme of compounds 11gaa, 12la. (a)NH₄OH, ethanol, glyoxal, RT; (b) NaH, substituted PhSO₂Cl, THF, 0°C.-RT; (c) t-BuLi (1.7 M in pentane), substituted benzoyl chloride, THF,−78° C.; (d) Bu₄NF, RT.

FIG. 12 depicts the synthetic scheme of compound 15xaa and 12xa. (a) 1.KOH, ethanol; 2. PhSO₂Cl, acetone; (b) NH₄OH, glyoxal, ethanol, RT; (c)NaH, PhSO₂Cl, THF, 0° C.-RT; (d) t-BuLi (1.7 M in pentane), benzoylchloride, THF, −78° C.; (e) NaOH, ethanol, H₂O, reflux.

FIG. 13 depicts synthetic scheme of 17ya. (a) 1. KOH, ethanol, 2.PhSO₂Cl, acetone, RT; (b) NH₄OH, glyoxal, ethanol, RT; (c) NaH, PhSO₂Cl,THF, 0° C.-RT; (d) t-BuLi (1.7 M in pentane), benzoyl chloride, THF,−78° C.; (e) NaOH, ethanol, H₂O, reflux.

FIG. 14 depicts synthetic scheme of 12fa. (a) NH₄OH, oxalaldehyde,ethanol, RT; (b) NaH, PhSO₂Cl, THF, 0° C.-RT; (c) t-BuLi,3,4,5-trimethoxybenzoyl chloride, THF, −78° C.; (d) Bu₄NF, THF, RT.

FIG. 15 depicts synthetic scheme of compound 55.

FIG. 16 Synthetic scheme of isoquinoline and quinoline based compounds.FIG. 16A depicts the synthetic scheme of isoquinoline derivatives.Reagents and conditions: a) arylboronic acid (1 equiv.), Pd(PPh₃)₄ (0.01equiv.), K₂CO₃, H₂O, DMF, 5 h; b) arylboronic acid (2.4 equiv.),Pd(PPh₃)₄ (0.04 equiv.), K₂CO₃, H₂O, DMF, 16 h; c) arylboronic acid (1.2equiv.), Pd(PPh₃)₄ (0.04 equiv.), K₂CO₃, H₂O, DMF, 16 h. FIG. 16Bdepicts the synthetic scheme of compounds 41 and 44. Reagents andconditions: a) p-fluorobenzenesulfonyl chloride, pyridine, pyridine, 80°C., 3 h; b) 5-indoleboronic acid (1.2 equiv.), Pd(PPh₃)₄ (0.02 equiv.),K₂CO₃, H₂O, DMF, 16 h. FIG. 16C depicts the synthetic scheme ofisoquinoline derivative 6d. FIG. 16D depicts the synthetic scheme ofisoquinoline derivative 6c. FIG. 16E depicts the synthetic scheme ofisoquinoline derivative 6b.

FIG. 17 depicts a standard solubility curve for ABI compound 12ga(dissolved in acetonitrile). X-axis is the amount of compound and y-axisis the m/z peak area.

FIG. 18 depicts the measured aqueous solubility for anti-tubulincompounds 1h, 1c, 66a, 2r-HCl, 5a, and 5c.

FIG. 19 depicts the structures of colchicine-binding site tubulininhibitors.

FIG. 20 depicts the ability of anti-tubulin compounds 1h, 1c, 2j, 66aand 5a to inhibit tubulin polymerization in vitro.

FIG. 21 depicts dose-response curves of 2-aryl-4-benzoyl-imidazolecompounds (ABIs) compared with other anticancer drugs and compounds onmultidrug resistant melanoma cell line (MDR cell) and the matchedsensitive parent cell line (Normal Melanoma cell). The large distancebetween the two curves for paclitaxel, vinblastine, and colchicineindicates that they were substrates for P-glycoprotein (P-gp). Theoverlapping two curves of each ABI compound indicate that the ABIcompounds were not substrates for P-gp and overcame multidrugresistance.

FIG. 22 presents the effect of ABI compounds on tubulin polymerizationin vitro. Tubulin (0.4 mg/assay) was exposed to 10 μM ABI compounds(vehicle control, 5% DMSO). Absorbance at 340 nm was monitored at 37° C.every minute for 15 min and demonstrated that ABI compounds 12da, 12cb,and 12 db inhibited tubulin polymerization in vitro.

FIG. 23 depicts B16-F1 melanoma colony formation assay in soft agarshowed that ABI compounds inhibited colony formation in aconcentration-dependent manner. FIG. 23A depicts representative picturesof control and each tested compound (12cb, 12da, and 12fb) at 100 nM.The diameter of each well was 35 mm. FIG. 23B depicts a quantifiedrepresentation of assay results for each tested compound (12cb, 12da,and 12fb). P value was calculated comparing with control using Student'st test by GraphPad Prism software. Columns, means of three replicates;bars, SD.

FIG. 24 depicts in vivo study of ABI compounds. FIG. 24A depicts the invivo activity of 12cb against B16-F1 melanoma tumors in C57/BL mice.FIG. 24B depicts the in vivo activity of 12fb against B16-F1 melanoma inC57BL/6 mice and SHO nude mice. Results showed that 12fb inhibitedmelanoma tumor growth in a dose-dependent manner. C57BL/6 mice bearingB16-F1 melanoma allograft (n=5 per group). Each mouse received 0.5×10⁶cells by s.c. injection into the flank. 30 μL i.p. daily treatments werestarted when tumor size reached ˜100 mm³. FIG. 24C depicts the in vivoactivity of 12fb against an A375 human melanoma xenograft. SHO nude micebearing an A375 human melanoma xenograft (n=5 per group). Each mousereceived 2.5×10⁶ cells by s.c. injection into the flank. 30 μL i.p.daily treatments were started when the tumor size reached is ˜150 mm³.Control, vehicle solution only; points, means; bars, SD. DTIC,(5-(3,3,-dimethyl-1-triazenyl)-imidazole-4-carboxamide, dacarbazine.

FIG. 25 depicts a competitive colchicine binding assay. FIG. 25A depictsa [³H]-colchicine competition-binding scintillation proximity assaywhich showed that 12cb competitively bound to tubulin colchicine bindingsite. FIG. 25B depicts representative graphs of cell cycle analysisusing flow cytometry showed that ABI compounds (examples shown for 12daand 12fb) arrested A375 cells in the G2/M phase after 24-h incubation.The effect and potency were similar to those of colchicine. FIG. 25Cshows quantified graphic depictions of cell cycle analysis. All testedcompounds (examples shown for 12cb, 12da, and 12fb) arrested A375 cellsin the G2/M phase in a dose-dependent manner. ABI 12da showed greaterpotency than did colchicine. FIG. 25D depicts a cell cycle analysisusing flow cytometry of A375 cells after being incubated with 12cb,12da, and 12fb at different concentrations for 24 h. Colchicine arrestedmost cells in the G2/M phase starting from 50 nM. 12cb, 12da, and 12fbalso arrested most cells in the G2/M phase starting from 200, 50, and200 nM respectively.

FIG. 26 depicts the effect of 17ya (top) and 55 (bottom) on tubulinpolymerization. Tubulin (0.4 mg) was exposed to test compounds (1 and 5μM). Absorbance at 340 nm was monitored every min for 15 min. 5 μMcolchicine was used as the positive control.

FIG. 27 depicts tumor inhibition of 17ya on a taxol-resistant prostatecancer (PC-3_TxR) xenograft model (top). The animals continued to gainweight (bottom) despite tumor regression indicating a lack of toxicityfor 17ya.

FIG. 28 depicts that compounds 1h, 2k, and 21 inhibit tubulinpolymerization via binding to the colchicine binding site on tubulin.(A) Structures of 1h (—H), 2k (—F), and 2l (—OH). (B) Effect of thecompounds on tubulin polymerization. Tubulin (0.4 mg) was exposed tocompounds 1h, 2k, and 2l (10 μM). Absorbance at 340 nm was monitoredevery min for 15 min. (C) Ability of 1h to compete for colchicine,vinblastine and paclitaxel binding sites on tubulin using massspectrometry competitive binding assay (n=3); bars, SD.

FIG. 29 depicts that compounds 1h, 2k and 2l arrested cells into G2/Mphase and induced apoptosis. (A) Representative graphs of cell cycleanalysis after compounds treatment for 24 h on PC-3 and A375 cells. (B)The changes in G2/M proportion induced by 1h, 2k, and 2l in PC-3 andA375 cells after 24 h treatment. (C) Ability of 1h, 2k, and 21 toenhance cytoplasmic DNA-Histone complex formation in 24 h (n=3); bars,SD. Colchicine and vinblastine were used as positive controls.

FIG. 30 depicts pharmacokinetic studies of 1h, 2k and 2l administeredi.p. in mice and rats. (A) Concentration-time curve of SMART compoundsin ICR mice (n=3); bars, SD. SMART compounds were administrated 15 mg/kgi.v. by tail vein injection. (B) Concentration-time curve of 1h and 2kin SD rats (n=4); bars, SD. Spague-Dawley rats were dosed 2.5 mg/kg i.v.with the formulation DMSO/PEG300 (1/4).

FIG. 31 presents in vivo anti-cancer efficacy (administered i.p.) andneurotoxicity of SMART compounds in mice. (A) SMART compounds efficacyfor PC-3 prostate tumor xenografted on nude mice (n=6-8). (B)Vinblastine efficacy for PC-3 prostate tumor xenografted on nude mice(n=8). This served as the positive control. (C) In vivo efficacy of 1hand 2k in nude mice bearing A375 melanoma xenografts (n=10). Nude micewere inoculated with 2.5×10⁶ PC-3 or A375 cells and dosed i.p. daily(SMART compounds) and q2d (vinblastine) after tumor formation (150-200mm³). Each point represents mean tumor volume for animals in each group.(D) In vivo neurotoxicity (rotarod test) of 1h in ICR mice (n=7 or 8).1h (5 and 15 mg/kg), vinblastine (0.5 mg/kg) and vehicle were given i.p.daily, and vinblastine was used as the positive control. The dosing wasstopped on day 31. *, p<0.05. Bars, SE.

FIG. 32 depicts molecular modeling of ABI compounds that target tubulinin the colchicine binding site. FIGS. 32A and 32B depict molecularmodeling of compound 12cb and 11cb, respectively.

FIG. 33 depicts microscopic images of immunofluorescence-labeledmicrotubules in WM-164 melanoma cells, which showed microtubule modalitywas dramatically changed after compound treatment for 18 h. Thisprovides visual proof that ABI compounds target tubulin and disruptfunctional microtubule formation.

FIG. 34 depicts the efficacy and tolerability of 6b and 6c in xenograftmodels after i.p. injection. A. PC-3 xenografts were treated withvehicle (qd), 6b (40 mg/kg, qd), or 6c (40 mg/kg, qd) for 3 weeks.Dosing vehicles were composed of 20% Captex200 in Tween80. The tumorvolumes (mm³) were plotted against time and are the means±SD from eightanimals. The tumor volumes were shown in left panel and body weightswere shown in right panel. B. The liver size (g) of each nude mouse wasmeasured after 3 weeks treatment. C. The number of white blood cells wascounted in whole blood collected from animal after 3 weeks treatment.

It will be appreciated that for simplicity and clarity of illustration,elements shown in the figures have not necessarily been drawn to scale.For example, the dimensions of some of the elements may be exaggeratedrelative to other elements for clarity. Further, where consideredappropriate, reference numerals may be repeated among the figures toindicate corresponding or analogous elements.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, this invention is directed to a compound of formula(I)

whereinA and C are each independently substituted or unsubstituted single-,fused- or multiple-ring aryl or (hetero)cyclic ring systems; substitutedor unsubstituted, saturated or unsaturated N-heterocycles; substitutedor unsubstituted, saturated or unsaturated S-heterocycles; substitutedor unsubstituted, saturated or unsaturated O-heterocycles; substitutedor unsubstituted, saturated or unsaturated cyclic hydrocarbons; orsubstituted or unsubstituted, saturated or unsaturated mixedheterocycles;

B is

R₁₀ and R₁₁ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br,I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;X is a bond, NH, C₁ to C₅ hydrocarbon, O, or S;Y is a bond, —C═O, —C═S, —C═N—NH₂, —C═N—OH, —CH—OH, —C═CH—CN, —C═N—CN,—CH═CH—, —C═C(CH₃)₂, —C═N—OMe, —(C═O)—NH, —NH—(C═O), —(C═O)—O, —O—(C═O),—(CH₂)₁₋₅—(C═O), (C═O)—(CH₂)₁₋₅, —(SO₂)—NH—, —NH—(SO₂)—, SO₂, SO or S;wherein said A and C rings are optionally substituted by 1-5substituents which are independently O-alkyl, O-haloalkyl, F, Cl, Br, I,haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O—alkyl, C(O)H, —C(O)NH₂ or NO₂;i is an integer between 0-5;l in an integer between 1-2;whereinif B is a benzene ring, a thiophene ring, a furane ring or an indolering then X is not a bond or CH₂, and A is not indole;if B is indole then X is not O; andor its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, if B of formula I is a thiazole ring then X is not abond.

In one embodiment, A in compound of Formula I is indolyl. In anotherembodiment A is 2-indolyl. In another embodiment A is phenyl. In anotherembodiment A is pyridyl. In another embodiment A is naphthyl. In anotherembodiment A is isoquinoline. In another embodiment, C in compound ofFormula I is indolyl. In another embodiment C is 2-indolyl. In anotherembodiment C is 5-indolyl. In another embodiment, B in compound ofFormula I is thiazole. In another embodiment, B in compound of Formula Iis thiazole; Y is CO and X is a bond. Non limiting examples of compoundof formula I are selected from:(2-(1H-Indol-2-yl)thiazol-4-yl)(1H-indol-2-yl)methanone (8),(2-(1H-indol-2-yl)thiazol-4-yl)(1H-indol-5-yl)methanone (21)

In one embodiment, this invention is directed to a compound of formula(Ia)

whereinA is substituted or unsubstituted single-, fused- or multiple-ring, arylor (hetero)cyclic ring systems; substituted or unsubstituted, saturatedor unsaturated N-heterocycles; substituted or unsubstituted, saturatedor unsaturated S-heterocycles; substituted or unsubstituted, saturatedor unsaturated O-heterocycles; substituted or unsubstituted, saturatedor unsaturated cyclic hydrocarbons; or substituted or unsubstituted,saturated or unsaturated mixed heterocycles;

B is

R₁, R₂ and R₃ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl,Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;R₁₀ and R₁₁ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br,I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl,

COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;

X is a bond, NH, C₁ to C₅ hydrocarbon, O, or S;Y is a bond, —C═O, —C═S, —C═N—NH₂, —C═N—OH, —CH—OH, —C═CH—CN,—C═N—CN, —CH═CH—, —C═C(CH₃)₂, —C═N—OMe, —(C═O)—NH, —NH—(C═O), —(C═O)—O,—O—(C═O), —(CH₂)₁₋₅—(C═O), (C═O)—(CH₂)₁₋₅, —(SO₂)—NH—, —NH—(SO₂)—, SO₂,SO or S;wherein said A ring is optionally substituted by 1-5 substituents whichare independently O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF₃,CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂,—(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branched alkyl, haloalkyl,alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph,C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;i is an integer between 0-5;l is an integer between 1-2;m is an integer between 1-3;whereinwherein if B is a benzene ring, a thiophene ring, a furane ring or anindole ring then X is not a bond or CH₂ and A is not indole;if B is indole then X is not O;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, if B of formula Ia is a thiazole ring then X is not abond.

In one embodiment, this invention is directed to a compound of formula(II):

wherein

B is

R₁, R₂, R₃, R₄, R₅ and R₆ are independently hydrogen, O-alkyl,O-haloalkyl, F, Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl,—(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph,—NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;R₁₀ and R₁₁ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br,I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;X is a bond, NH, C₁ to C₅ hydrocarbon, O, or S;Y is a bond, —C═O, —C═S, —C═N—NH₂, —C═N—OH, —CH—OH, —C═CH—CN,—C═N—CN, —CH═CH—, C═CH(CH₃)₂, —C═N—OMe, —(C═O)—NH, —NH—(C═O), —(C═O)—O,—O—(C═O), —(CH₂)₁₋₅—(C═O), (C═O)—(CH₂)₁₋₅, —(SO₂)—NH—, —NH—(SO₂)—, SO₂,SO or S;i is an integer between 0-5;l is an integer between 1-2;n is an integer between 1-3; andm is an integer between 1-3;whereinif B is indole then X is not O;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, if B of formula II is a thiazole ring then X is not abond.

In one embodiment, this invention is directed to a compound of formula(III)

wherein

B is

R₄, R₅ and R₆ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl,Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂; andR₁₀ and R₁₁ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br,I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;X is a bond, NH, C_(I) to C₅ hydrocarbon, O, or S;Y is a bond, —C═O, —C═S, —C═N—NH₂, —C═N—OH, —CH—OH, —C═CH—CN, —C═N—CN,—CH═CH—, C═CH(CH₃)₂, —C═N—OMe, —(C═O)—NH, —NH—(C═O), —(C═O)—O, —O—(C═O),—(CH₂)₁₋₅—(C═O), (C═O)—(CH₂)₁₋₅, —(SO₂)—NH—, —NH—(SO₂)—, SO₂, SO or S;i is an integer between 0-5;l is an integer between 1-2; andn is an integer between 1-3;whereinif B is indole then X is not O;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, if B of formula III is a thiazole ring then X is nota bond.

In one embodiment, this invention is directed to a compound of formula(IV)

wherein ring A is an indolyl;

B is

R₁ and R₂ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br,I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;R₁₀ and R₁₁ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br,I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;X is a bond, NH, C₁ to C₅ hydrocarbon, O, or S;Y is a bond, C═O, —C═S, —C═N—NH₂, —C═N—OH, —CH—OH, —C═CH—CN, —C═N—CN,—CH═CH—, C═CH(CH₃)₂, —C═N—OMe, —(C═O)—NH, —NH—(C═O), —(C═O)—O, —O—(C═O),—(CH₂)₁₋₅—(C═O), (C═O)—(CH₂)₁₋₅, —(SO₂)—NH—, —NH—(SO₂)—, SO₂, SO or S;wherein said A is optionally substituted by O-alkyl, O-haloalkyl, F, Cl,Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂; andi is an integer between 0-5;l is an integer between 1-2; andm is an integer between 1-4;whereinif B is a benzene ring, a thiophene ring, a furane ring or an indolering then X is not a bond or CH₂;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, if B of formula IV is a thiazole ring then X is not abond.

In another embodiment, the indolyl of ring A of formula IV is attachedto one of its 1-7 positions to X or direct to B if X is a bond (i.enothing).

In one embodiment, this invention is directed to a compound of formulaIV(a)

B is

R₁, R₂, R₄ and R₅ are independently hydrogen, O-alkyl, O-haloalkyl, F,Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂; andR₁₀ and R₁₁ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br,I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;X is a bond, NH, C₁ to C₅ hydrocarbon, O, or S;Y is a bond or C═O, —C═S, —C═N—NH₂, —C═N—OH, —CH—OH, —C═CH—CN, —C═N—CN,—CH═CH—, C═CH(CH₃)₂, —C═N—OMe, —(C═O)—NH, —NH—(C═O), —(C═O)—O, —O—(C═O),—(CH₂)₁₋₅—(C═O), (C═O)—(CH₂)₁₋₅, —(SO₂)—NH—, —NH—(SO₂)—, SO₂, SO or S;i is an integer between 0-5;l is an integer between 1-2;n is an integer between 1-2; andm is an integer between 1-4;whereinif B is a benzene ring, a thiophene ring, a furane ring or an indolering then X is not a bond or CH₂;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, if B of formula IVa is a thiazole ring then X is nota bond.

In one embodiment, this invention is directed to a compound of formula(V)

B is

R₄, R₅ and R₆ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl,Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;R₁₀ and R₁₁ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br,I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;i is an integer between 1-5;l is an integer between 1-2; andn is an integer between 1-3;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In another embodiment, B of formula V is not a thiazole

In another embodiment, B of formula V is not an oxazole. In anotherembodiment, B of formula V is not an oxazoline. In another embodiment, Bof formula V is not an imidazole. In another embodiment, B of formula Vis not a thiazole, oxazole, oxazoline or imidazole.

In one embodiment, this invention is directed to the followingcompounds:

Formula V

R₄, R₅ and Compound B R₆ 1a

H 1b

H 1c

H 1d

H 1e

H 1f

H 1g

H 1h

H 1i

H 1k

H 1l

H 35a

H 36a

H

In one embodiment, this invention is directed to a compound of formula(VI)

whereinR₄, R₅ and R₆ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl,Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂; andY is a bond or C═O, —C═S, —C═N—NH₂, —C═N—OH, —CH—OH, —C═CH—CN,—C═N—CN, —CH═CH—, C═CH(CH₃)₂, —C═N—OMe, —(C═O)—NH, —NH—(C═O), —(C═O)—O,—O—(C═O), —(CH₂)₁₋₅—(C═O), (C═O)—(CH₂)₁₋₅, —(SO₂)—NH—, —NH—(SO₂)—, SO₂,SO or S;n is an integer between 1-3; andi is an integer from 1-5;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, this invention is directed to the followingcompounds:

Formula VI

Compound Y R₄, R₅ and R₆ 1h —C═O H 2a —C═C(CH₃)₂ H 2b —CH—OH H 2c—C═CH—CN H (cis and trans) 2d —C═N—NH₂ H 2e —C═N—OH H 2f —C═N—OMe H (cisand trans) 2g —(C═O)—NH— H 2h —NH—(C═O)— H 2i nothing H 2j —C═N—CN H(cis and trans) 2k C═O R₄ = R₆ = H R₅ = p-F 2l C═O R₄ = R₆ = H R₅ = p-OH2m C═O R₄ = R₆ = H R₅ = p-CH₃ 2n C═O R₄ = R₆ = H R₅ = p-CH₂—CN 2o C═O R₄= R₆ = H R₅ = p-N(CH₃)₂ 2p C═O R₄ = m-F; R₅ = p-F; R₆ = m-F; n = 1 2qC═O R₄ = R₆ = H R₅ = p-CH₂—(C═O)NH₂ 2r C═O R₄ = R₆ = H R₅ = p-CH₂NH₂ 2sC═O R₄ = R₆ = H R₅ = p-CH₂NH—CH₃ 2t C═O R₄ = m-OMe; R₅ = p-OMe; R₆ =m-OMe; n = 1 2u C═O R₄ = R₆ = H R₅ = p-CH₂NMe₂

In one embodiment, this invention is directed to compound 3a:

In one embodiment, this invention is directed to compound 3b:

In one embodiment, this invention is directed to a compound of formula(VII)

whereinY is a bond or C═O, —C═S, —C═N—NH₂, —C═N—OH, —CH—OH, —C═CH—CN,—C═N—CN, —CH═CH—, C═CH(CH₃)₂, —C═N—OMe, —(C═O)—NH, —NH—(C═O), —(C═O)—O,—O—(C═O), —(CH₂)₁₋₅—(C═O), (C═O)—(CH₂)₁₋₅, —(SO₂)—NH—, —NH—(SO₂)—, SO₂,SO or S;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, this invention is directed to the followingcompounds:

Formula VII

Compound Y 4a S 4b SO₂ 4c SO 4d —(SO₂)—NH—

In one embodiment, this invention is directed to a compound of formula(VIII)

whereinR₄, R₅ and R₆ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl,Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;

Q is S, O or NH;

i is an integer between 0-5; andn is an integer between 1-3;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, this invention is directed to the followingcompounds:

Formula VIII

Compound R₄ R₅ R₆ Q 5a H H H S n = 1 5b H p-CH₃ H S n = 1 5c H p-F H S n= 1

In one embodiment, this invention is directed to a compound of formula(IX)

whereinR₄ and R₅ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br,I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂,—(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branched alkyl, haloalkyl,alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph,C(O)O-alkyl, C(O)H, —(O)NH₂ or NO₂;A′ is halogen; substituted or unsubstituted single-, fused- ormultiple-ring, aryl or (hetero)cyclic ring systems; substituted orunsubstituted, saturated or unsaturated N-heterocycles; substituted orunsubstituted, saturated or unsaturated S-heterocycles; substituted orunsubstituted, saturated or unsaturated O-heterocycles; substituted orunsubstituted, saturated or unsaturated cyclic hydrocarbons; orsubstituted or unsubstituted, saturated or unsaturated mixedheterocycles; wherein said A′ ring is optionally substituted by 1-5substituents which are independently O-alkyl, O-haloalkyl, F, Cl, Br, I,haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;i is an integer between 1-5; andn is an integer between 1-3;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, a compound of Formula IX is represented by thestructures of the following compounds:

Formula IX

Compound A′ R₄, R₅ 6a

H 6b

H 6c

H 6d Cl H

In one embodiment A′ of formula IX is a phenyl. In another embodiment A′of formula IX is substituted phenyl. In another embodiment A′ of formulaIX is a halogen. In another embodiment the substitution of A′ ishalogen. In another embodiment the substitution is 4-F. In anotherembodiment the substitution is 3,4,5-(OCH₃)₃. In another embodiment, A′of formula IX is substituted or unsubstituted 5-indolyl. In anotherembodiment, A′ of formula IX is substituted or unsubstituted 2-indolyl.In another embodiment, A′ of formula IX is substituted or unsubstituted3-indolyl. In another embodiment, compounds of formula IX are presentedin FIG. 16A.

In one embodiment, this invention is directed to a compound of formula(IXa)

whereinR₄ and R₅ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br,I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —(O)NH₂ or NO₂;A′ is halogen; substituted or unsubstituted single-, fused- ormultiple-ring, aryl or (hetero)cyclic ring systems; substituted orunsubstituted, saturated or unsaturated N-heterocycles; substituted orunsubstituted, saturated or unsaturated S-heterocycles; substituted orunsubstituted, saturated or unsaturated O-heterocycles; substituted orunsubstituted, saturated or unsaturated cyclic hydrocarbons; orsubstituted or unsubstituted, saturated or unsaturated mixedheterocycles; wherein said A′ ring is optionally substituted by 1-5substituents which are independently O-alkyl, O-haloalkyl, F, Cl, Br, I,haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;i is an integer between 1-5; andn is an integer between 1-3;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment A′ of formula IXa is a phenyl. In another embodimentA′ of formula IXa is substituted phenyl. In another embodiment A′ offormula IXa is a halogen. In another embodiment the substitution of A′is halogen. In another embodiment the substitution is 4-F. In anotherembodiment the substitution is 3,4,5-(OCH₃)₃. In another embodiment, A′of formula IXa is substituted or unsubstituted 5-indolyl. In anotherembodiment, A′ of formula IXa is substituted or unsubstituted 2-indolyl.In another embodiment, A′ of formula IXa is substituted or unsubstituted3-indolyl.

In another embodiment, a compound of formula IXa is1-chloro-7-(4-fluorophenyl)isoquinoline. In another embodiment, acompound of formula IXa is7-(4-fluorophenyl)-1-(1H-indol-5-yl)isoquinoline. In another embodiment,a compound of formula IXa is7-(4-fluorophenyl)-1-(3,4,5-trimethoxyphenyl)isoquinoline. In anotherembodiment, a compound of formula IXa is1,7-bis(4-fluorophenyl)isoquinoline (40). In another embodiment, acompound of formula IXa is 1,7-bis(3,4,5-trimethoxyphenyl)isoquinoline.In another embodiment, a compound of formula IXa is1-(4-fluorophenyl)-7-(3,4,5-trimethoxyphenyl)isoquinoline. In anotherembodiment, a compound of formula IXa is1-(1H-indol-5-yl)-7-(3,4,5-trimethoxyphenyl)isoquinoline. In anotherembodiment, a compound of formula IXa is1-chloro-7-(3,4,5-trimethoxyphenyl)isoquinoline.

In one embodiment, this invention is directed to a compound representedby the structure of formula XI:

whereinX is a bond, NH or S;

Q is O, NH or S; and

A is substituted or unsubstituted single-, fused- or multiple-ring arylor (hetero)cyclic ring systems; substituted or unsubstituted, saturatedor unsaturated N-heterocycles; substituted or unsubstituted, saturatedor unsaturated S-heterocycles; substituted or unsubstituted, saturatedor unsaturated O-heterocycles; substituted or unsubstituted, saturatedor unsaturated cyclic hydrocarbons; or substituted or unsubstituted,saturated or unsaturated mixed heterocycles; wherein said A ring isoptionally substituted by 1-5 1-5 substituents which are independentlyO-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂,hydroxyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃,C₁-C₅ linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl,—OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ orNO₂; andi is an integer from 0-5;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment if Q of Formula XI is S, then X is not a bond.

In one embodiment, A of compound of Formula XI is Ph. In anotherembodiment, A of compound of Formula XI is substituted Ph. In anotherembodiment, the substitution is 4-F. In another embodiment, thesubstitution is 4-Me. In another embodiment, Q of compound of Formula XIis S. In another embodiment, X of compound of Formula XI is NH. Nonlimiting examples of compounds of Formula XI are selected from:(2-(Phenylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (5a),(2-(p-Tolylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (5b),(2-(p-Fluorophenylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(5c), (2-(Phenylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanonehydrochloride salt (5Ha),(2-(p-Tolylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanonehydrochloride salt (5Hb),(2-(p-Fluorophenylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanonehydrochloride salt (5Hc).

In one embodiment, this invention is directed to a compound representedby the structure of formula XI(a):

wherein R₄ and R₅ are independently hydrogen, O-alkyl, O-haloalkyl, F,Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;i is an integer from 0-5; andn is an integer between 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, this invention is directed to a compound representedby the structure of formula XI(b):

wherein R₄ and R₅ are independently hydrogen, O-alkyl, O-haloalkyl, F,Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;i is an integer from 0-5; andn is an integer between 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, this invention is directed to a compound representedby the structure of formula XI(c):

wherein R₄ and R₅ are independently hydrogen, O-alkyl, O-haloalkyl, F,Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;i is an integer from 0-5; andn is an integer between 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, this invention is directed to a compound representedby the structure of formula XI(d):

wherein R⁴ and R⁵ and R₅ are independently hydrogen, O-alkyl,O-haloalkyl, F, Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl,—(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph,—NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;i is an integer from 0-5; andn is an integer between 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, this invention is directed to a compound representedby the structure of formula XI(e):

wherein R₄ and R₅ are independently hydrogen, O-alkyl, O-haloalkyl, F,Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;i is an integer from 0-5; andn is an integer between 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In another embodiment, a compound of formula XI is represented by thestructure of compound 55:

In another embodiment, a compound of formula XI is represented by thestructure of compound 17ya:

In one embodiment, this invention provides a compound represented by thefollowing structures:

compound structure 8

9

10

11

12

13

14

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

32

33

34

35

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

It is well understood that in structures presented in this inventionwherein the nitrogen atom has less than 3 bonds, H atoms are present tocomplete the valence of the nitrogen.

In one embodiment the A, A′ and/or C groups of formula I, I(a), IV, IX,IX(a) and XI are independently substituted and unsubstituted furanyl,indolyl, pyridinyl, phenyl, biphenyl, triphenyl, diphenylmethane,adamantane-yl, fluorene-yl, and other heterocyclic analogs such as thoseidentified above (e.g., pyrrolyl, pyrazolyl, imidazolyl, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl,pyrrolizinyl, indolyl, isoquinolinyl, quinolinyl, isoquinolinyl,benzimidazolyl, indazolyl, quinolizinyl, cinnolinyl, quinazolinyl,phthalazinyl, naphthyridinyl, quinoxalinyl, oxiranyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, furanyl, pyrylium,benzofuranyl, benzodioxolyl, thiranyl, thietanyl,tetrahydrothiophene-yl, dithiolanyl, tetrahydrothiopyranyl,thiophene-yl, thiepinyl, thianaphthenyl, oxathiolanyl, morpholinyl,thioxanyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl,oxadiaziolyl).

In one embodiment, the most preferred A, A′ and/or C groups issubstituted and unsubstituted phenyl. In one embodiment, the mostpreferred A, A′ and/or C groups is substituted and unsubstitutedisoquinolinyl. In one embodiment, the A, A′ and/or C groups includesubstituted and unsubstituted indolyl groups; most preferably,substituted and unsubstituted 3-indolyl and 5-indolyl.

In one embodiment, the A, A′ and/or C groups of formula I, I(a), IV, IX,IX(a) and XI can be substituted or unsubstituted. Thus, although theexemplary groups recited in the preceding paragraph are unsubstituted,it should be appreciated by those of skill in the art that these groupscan be substituted by one or more, two or more, three or more, and evenup to five substituents (other than hydrogen).

In one embodiment, the most preferred A, A′ and/or C groups aresubstituted by 3,4,5-trimethoxyphenyl. In another embodiment the A, A′and/or C groups are substituted by alkoxy. In another embodiment the A,A′ and/or C groups are substituted by methoxy. In another embodiment theA, A′ and/or C groups are substituted by alkyl. In another embodimentthe A, A′ and/or C groups are substituted by methyl. In anotherembodiment the A, A′ and/or C groups are substituted by halogen. Inanother embodiment, the A, A′ and/or C groups are substituted by F. Inanother embodiment, the A, A′ and/or C groups are substituted by Cl. Inanother embodiment, the A, A′ and/or C rings are substituted by Br.

The substituents of these A, A′ and/or C groups of formula I, I(a), IV,IX, IX(a) and XI are independently selected from the group of hydrogen(e.g., no substitution at a particular position), hydroxyl, an aliphaticstraight- or branched-chain C₁ to C₁₀ hydrocarbon, alkoxy, haloalkoxy,aryloxy, nitro, cyano, alkyl-CN, halo (e.g., F, Cl, Br, I), haloalkyl,dihaloalkyl, trihaloalkyl, COOH, C(O)Ph, C(O)-alkyl, C(O)O-alkyl, C(O)H,C(O)NH₂, —OC(O)CF₃, OCH₂Ph, amino, aminoalkyl, alkylamino, mesylamino,dialkylamino, arylamino, amido, NHC(O)-alkyl, urea, alkyl-urea,alkylamido (e.g., acetamide), haloalkylamido, arylamido, aryl, and C₅ toC₇ cycloalkyl, arylalkyl, and combinations thereof. Single substituentscan be present at the ortho, meta, or para positions. When two or moresubstituents are present, one of them is preferably, though notnecessarily, at the para position.

In one embodiment the B group of formula I, I(a), II, III, IV, IVa and Vis selected from substituted or unsubstituted-thiazole, thiazolidine,oxazole, oxazoline, oxazolidine, benzene, pyrimidine, imidazole,pyridine, furan, thiophene, isoxazole, piperidine, pyrazole, indole andisoquinoline, wherein said B ring is linked via any two position of thering to X and Y or directly to the, phenyl, indolyl A, and/or C rings.

In one embodiment the B group of formula I, I(a), II, III, IV, IVa and Vis unsubstituted. In another embodiment the B group of formula I, I(a),II, III, IV, IVa and V is:

In another embodiment the B group of formula I, I(a), II, III, IV, IVaand V is substituted. In another embodiment the B group of formula I,I(a), II, III, IV, IVa and V is:

wherein R₁₀ and R₁₁ are independently hydrogen, O-alkyl, O-haloalkyl, F,Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂.

In another embodiment the B group is

(thiazole). In another embodiment the B group is

(thiazole). In another embodiment the B group is

(thiazolidine). In another embodiment the B group is

(oxazole). In another embodiment the B group is

(oxazoline). In another embodiment the B group is

(oxazolidine). In another embodiment the B group is

(benzene). In another embodiment the B group is

(benzene). In another embodiment the B group is

(pyrimidine). In another embodiment the B group is

(imidazole). In another embodiment the B group is

(pyridine). In another embodiment the B group is

(furan). In another embodiment the B group is

(thiophene). In another embodiment the B group is

(isoxazole). In another embodiment the B group is

(piperidine). In another embodiment the B group is

(piperidine). In another embodiment the B group is

(pyrazole). In another embodiment the B group is

(indole). In another embodiment the B group is

(isoquinoline).

In one embodiment the B group of formula I, I(a), II, III, IV, IVa and Vis substituted by R10 and R11. In another embodiment, R₁₀ and R₁₁ areboth hydrogens. In another embodiment, R₁₀ and R₁₁ are independentlyO-alkyl. In another embodiment, R₁₀ and R₁₁ are independentlyO-haloalkyl. In another embodiment, R₁₀ and R₁₁ are independently F. Inanother embodiment, R₁₀ and R₁₁ are independently Cl. In anotherembodiment, R₁₀ and R₁₁ are independently Br. In another embodiment, R₁₀and R₁₁ are independently I. In another embodiment, R₁₀ and R₁₁ areindependently haloalkyl. In another embodiment, R₁₀ and R₁₁ areindependently CF₃. In another embodiment, R₁₀ and R₁₁ are independentlyCN. In another embodiment, R₁₀ and R₁₁ are independently —CH₂CN. Inanother embodiment, R₁₀ and R₁₁ are independently NH₂. In anotherembodiment, R₁₀ and R₁₁ are independently hydroxyl. In anotherembodiment, R₁₀ and R₁₃ are independently —(CH₂)_(i)NHCH₃. In anotherembodiment, R₁₀ and R₁₁ are independently —(CH₂)_(i)NH₂. In anotherembodiment, R₁₀ and R₁₁ are independently —(CH₂)_(i)N(CH₃)₂. In anotherembodiment, R₁₀ and R₁₁ are independently —OC(O)CF₃. In anotherembodiment, R₁₀ and R₁₁ are independently C₁-C₅ linear or branchedalkyl. In another embodiment, R₁₀ and R₁₁ are independently C₁-C₅ linearor branched haloalkyl. In another embodiment, R₁₀ and R₁₁ areindependently C₁-C₅ linear or branched alkylamino. In anotherembodiment, R₁₀ and R₁₁ are independently C₁-C₅ linear or branchedaminoalkyl. In another embodiment, R₁₀ and R₁₁ are independently—OCH₂Ph. In another embodiment, R₁₀ and R₁₁ are independently—NHCO-alkyl. In another embodiment, R₁₀ and R₁₁ are independently COOH.In another embodiment, R₁₀ and R₁₁ are independently —C(O)Ph. In anotherembodiment, R₁₀ and R₁₁ are independently C(O)O-alkyl. In anotherembodiment, R₁₀ and R₁₁ are independently C(O)H. In another embodiment,R₁₀ and R₁₁ are independently —C(O)NH₂. In another embodiment, R₁₀ andR₁₁ are independently NO₂.

In another embodiment the B group of formula I, I(a), II, III, IV, IVaand V is

(thiazole), wherein R₁₀ and R₁₁ are independently H and l is 1. Inanother embodiment, R₁₀ and R₁₁ are independently O-alkyl. In anotherembodiment, R₁₀ and R₁₁ are independently O-haloalkyl. In anotherembodiment, R₁₀ and R₁₁ are independently F. In another embodiment, R₁₀and R₁₁ are independently Cl. In another embodiment, R₁₀ and R₁₁ areindependently Br. In another embodiment, R₁₀ and R₁₁ are independentlyI. In another embodiment, R₁₀ and R₁₁ are independently haloalkyl. Inanother embodiment, R₁₀ and R₁₁ are independently CF₃. In anotherembodiment, R₁₀ and R₁₁ are independently CN. In another embodiment, R₁₀and R₁₁ are independently —CH₂CN. In another embodiment, R₁₀ and R₁₁ areindependently NH₂. In another embodiment, R₁₀ and R₁₁ are independentlyhydroxyl. In another embodiment, R₁₀ and R₁₁ are independently—(CH₂)_(i)NHCH₃. In another embodiment, R₁₀ and R₁₁ are independently—(CH₂)_(i)NH₂. In another embodiment, R₁₀ and R₁₁ are independently—(CH₂)_(i)N(CH₃)₂. In another embodiment, R₁₀ and R₁₁ are independently—OC(O)CF₃. In another embodiment, R₁₀ and R₁₁ are independently C₁-C₅linear or branched alkyl. In another embodiment, R₁₀ and R₁₁ areindependently C₁-C₅ linear or branched haloalkyl. In another embodiment,R₁₀ and R₁₁ are independently C₁-C₅ linear or branched alkylamino. Inanother embodiment, R₁₀ and R₁₁ are independently C₁-C₅ linear orbranched aminoalkyl. In another embodiment, R₁₀ and R₁₁ areindependently —OCH₂Ph. In another embodiment, R₁₀ and R₁₁ areindependently —NHCO-alkyl. In another embodiment, R₁₀ and R₁₁ areindependently COOH. In another embodiment, R₁₀ and R₁₁ are independently—C(O)Ph. In another embodiment, R₁₀ and R₁₁ are independentlyC(O)O-alkyl. In another embodiment, R₁₀ and R₁₁ are independently C(O)H.In another embodiment, R₁₀ and R₁₁ are independently —C(O)NH₂. Inanother embodiment, R₁₀ and R₁₁ are independently NO₂.

In another embodiment the B group of formula I, I(a), II, III, IV, IVaand V is

(imidazole), wherein R₁₀ and R₁₁ are independently H and l is 1. Inanother embodiment, R₁₀ and R₁₁ are independently O-alkyl. In anotherembodiment, R₁₀ and R₁₁ are independently O-haloalkyl. In anotherembodiment, R₁₀ and R₁₁ are independently F. In another embodiment, R₁₀and R₁₁ are independently Cl. In another embodiment, R₁₀ and R₁₁ areindependently Br. In another embodiment, R₁₀ and R₁₁ are independentlyI. In another embodiment, R₁₀ and R₁₁ are independently haloalkyl. Inanother embodiment, R₁₀ and R₁₁ are independently CF₃. In anotherembodiment, R₁₀ and R₁₁ are independently CN. In another embodiment, R₁₀and R₁₁ are independently —CH₂CN. In another embodiment, R₁₀ and R₁₁ areindependently NH₂. In another embodiment, R₁₀ and R₁₁ are independentlyhydroxyl. In another embodiment, R₁₀ and R₁₁ are independently—(CH₂)_(i)NHCH₃. In another embodiment, R₁₀ and R₁₁ are independently—(CH₂)_(i)NH₂. In another embodiment, R₁₀ and R₁₁ are independently—(CH₂)_(i)N(CH₃)₂. In another embodiment, R₁₀ and R₁₁ are independently—OC(O)CF₃. In another embodiment, R₁₀ and R₁₁ are independently C₁-C₅linear or branched alkyl. In another embodiment, R₁₀ and R₁₁ areindependently C₁-C₅ linear or branched haloalkyl. In another embodiment,R₁₀ and R₁₁ are independently C₁-C₅ linear or branched alkylamino. Inanother embodiment, R₁₀ and R₁₁ are independently C₁-C₅ linear orbranched aminoalkyl. In another embodiment, R₁₀ and R₁₁ areindependently —OCH₂Ph. In another embodiment, R₁₀ and R₁₁ areindependently —NHCO-alkyl. In another embodiment, R₁₀ and R₁₁ areindependently COOH. In another embodiment, R₁₀ and R₁₁ are independently—C(O)Ph. In another embodiment, R₁₀ and R₁₁ are independentlyC(O)O-alkyl. In another embodiment, R₁₀ and R₁₁ are independently C(O)H.In another embodiment, R₁₀ and R₁₁ are independently —C(O)NH₂. Inanother embodiment, R₁₀ and R₁₁ are independently NO₂.

In another embodiment the B group of formula I, I(a), II, III, IV, IVaand V is

(isoquinoline), wherein R₁₀ and R₁₁ are independently H and l is 1. Inanother embodiment, R₁₀ and R₁₁ are independently O-alkyl. In anotherembodiment, R₁₀ and R₁₁ are independently O-haloalkyl. In anotherembodiment, R₁₀ and R₁₁ are independently F. In another embodiment, R₁₀and R₁₁ are independently Cl. In another embodiment, R₁₀ and R₁₁ areindependently Br. In another embodiment, R₁₀ and R₁₁ are independentlyI. In another embodiment, R₁₀ and R₁₁ are independently haloalkyl. Inanother embodiment, R₁₀ and R₁₁ are independently CF₃. In anotherembodiment, R₁₀ and R₁₁ are independently CN. In another embodiment, R₁₀and R₁₁ are independently —CH₂CN. In another embodiment, R₁₀ and R₁₁ areindependently NH₂. In another embodiment, R₁₀ and R₁₁ are independentlyhydroxyl. In another embodiment, R₁₀ and R₁₁ are independently—(CH₂)_(i)NHCH₃. In another embodiment, R₁₀ and R₁₁ are independently—(CH₂)_(i)NH₂. In another embodiment, R₁₀ and R₁₁ are independently—(CH₂)_(i)N(CH₃)₂. In another embodiment, R₁₀ and R₁₁ are independently—OC(O)CF₃. In another embodiment, R₁₀ and R₁₁ are independently C₁-C₅linear or branched alkyl. In another embodiment, R₁₀ and R₁₁ areindependently C₁-C₅ linear or branched haloalkyl. In another embodiment,R₁₀ and R₁₁ are independently C₁-C₅ linear or branched alkylamino. Inanother embodiment, R₁₀ and R₁₁ are independently C₁-C₅ linear orbranched aminoalkyl. In another embodiment, R₁₀ and R₁₁ areindependently —OCH₂Ph. In another embodiment, R₁₀ and R₁₁ areindependently —NHCO-alkyl. In another embodiment, R₁₀ and R₁₁ areindependently COOH. In another embodiment, R₁₀ and R₁₁ are independently—C(O)Ph. In another embodiment, R₁₀ and R₁₁ are independentlyC(O)O-alkyl. In another embodiment, R₁₀ and R₁₁ are independently C(O)H.In another embodiment, R₁₀ and R₁₁ are independently —C(O)NH₂. Inanother embodiment, R₁₀ and R₁₁ are independently NO₂.

In one embodiment, the X bridge of formula I, Ia, II, III, IV, IVa andXI is a bond. In another embodiment, the X bridge is NH. In anotherembodiment, the X bridge is C₁ to C₅ hydrocarbon. In another embodiment,the X bridge is CH₂. In another embodiment, the X bridge is —CH₂—CH₂—.In another embodiment, the X bridge is O. In another embodiment, the Xbridge is S.

In one embodiment, the Y bridge of formula I, Ia, II, III, IV, IVa, VI,and VII is C═O. In another embodiment, the Y bridge is C═S. In anotherembodiment, the Y bridge is C═N(NH₂)—. In another embodiment, the Ybridge is —C═NOH. In another embodiment, the Y bridge is —CH—OH. Inanother embodiment, the Y bridge is —C═CH—(CN). In another embodiment,the Y bridge is —C═N(CN). In another embodiment, the Y bridge is—C═CH(CH₃)₂. In another embodiment, the Y bridge is —C═N—OMe. In anotherembodiment, the Y bridge is —(C═O)NH—. In another embodiment, the Ybridge is —NH(C═O)—. In another embodiment, the Y bridge is —(C═O)—O. Inanother embodiment, the Y bridge is —O—(C═O). In another embodiment, theY bridge is —(CH₂)₁₋₅—(C═O). In another embodiment, the Y bridge is—(C═O)—(CH₂)₁₋₅. In another embodiment, the Y bridge is S. In anotherembodiment, the Y bridge is SO. In another embodiment, the Y bridge isSO₂. In another embodiment, the Y bridge is —CH═CH—. In anotherembodiment, the Y bridge is —(SO₂)—NH—. In another embodiment, the Ybridge is —NH—(SO₂)—.

In one embodiment, R₁, R₂, R₃, R₄, R₅ and R₆ of formula Ia, II, III, IV,IV(a), V, VI, VIII, IX, IX(a), XI(a), XI(b), XI(c), XI(d) and XI(e) areindependently hydrogen. In another embodiment, R₁, R₂, R₃, R₄, R₅ and R₆are independently O-alkyl. In another embodiment, R₁, R₂, R₃, R₄, R₅ andR₆ are independently O-haloalkyl. In another embodiment, R₁, R₂, R₃, R₄,R₅ and R₆ are independently F. In another embodiment, R₁, R₂, R₃, R₄, R₅and R₆ are independently Cl. In another embodiment, R₁, R₂, R₃, R₄, R₅and R₆ are independently Br. In another embodiment, R₁, R₂, R₃, R₄, R₅and R₆ are independently I. In another embodiment, R₁, R₂, R₃, R₄, R₅and R₆ are independently haloalkyl. In another embodiment, R₁, R₂, R₃,R₄, R₅ and R₆ are independently CF₃. In another embodiment, R₁, R₂, R₃,R₄, R₅ and R₆ are independently CN. In another embodiment, R₁, R₂, R₃,R₄, R₅ and R₆ are independently —CH₂CN. In another embodiment, R₁, R₂,R₃, R₄, R₅ and R₆ are independently NH₂. In another embodiment, R₁, R₂,R₃, R₄, R₅ and R₆ are independently hydroxyl. In another embodiment, R₁,R₂, R₃, R₄, R₅ and R₆ are independently —(CH₂)_(i)NHCH₃. In anotherembodiment, R₁, R₂, R₃, R₄, R₅ and R₆ are independently —(CH₂)_(i)NH₂.In another embodiment, R₁, R₂, R₃, R₄, R₅ and R₆ are independently—(CH₂)_(i)N(CH₃)₂. In another embodiment, R₁, R₂, R₃, R₄, R₅ and R₆ areindependently —OC(O)CF₃. In another embodiment, R₁, R₂, R₃, R₄, R₅ andR₆ are independently C₁-C₅ linear or branched alkyl. In anotherembodiment, R₁, R₂, R₃, R₄, R₅ and R₆ are independently haloalkyl. Inanother embodiment, R₁, R₂, R₃, R₄, R₅ and R₆ are independentlyalkylamino. In another embodiment, R₁, R₂, R₃, R₄, R₅ and R₆ areindependently aminoalkyl. In another embodiment, R₁, R₂, R₃, R₄, R₅ andR₆ are independently —OCH₂Ph. In another embodiment, R₁, R₂, R₃, R₄, R₅and R₆ are independently —NHCO-alkyl. In another embodiment, R₁, R₂, R₃,R₄, R₅ and R₆ are independently COOH. In another embodiment, R₁, R₂, R₃,R₄, R₅ and R₆ are independently —C(O)Ph. In another embodiment, R₁, R₂,R₃, R₄, R₅ and R₆ are independently C(O)O-alkyl. In another embodiment,R₁, R₂, R₃, R₄, R₅ and R₆ are independently C(O)H. In anotherembodiment, R₁, R₂, R₃, R₄, R₅ and R₆ are independently —C(O)NH₂. Inanother embodiment, R₁, R₂, R₃, R₄, R₅ and R₆ are independently NO₂.

In one embodiment, this invention is directed to a compound of formulaXII:

wherein,P and Q are independently H or

W is C═O, C═S, SO₂ or S═O;

wherein at least one of Q or P is not hydrogen;R₁ and R₄ are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl,aminoalkyl, OCH₂Ph, OH, CN, NO₂, —NHCO-alkyl, COOH, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂; C(O)O-alkyl or C(O)H; wherein at leastone of R₁ and R₄ is not hydrogen;R₂ and R₅ are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl,aminoalkyl, OCH₂Ph, OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkyl orC(O)H;m is an integer between 1-4;i is an integer between 0-5; andn is an integer between 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, this invention is directed to a compound of formulaXIII:

wherein

Z is O or S;

R₁ and R₄ are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl,aminoalkyl, OCH₂Ph, OH, CN, NO₂, —NHCO-alkyl, haloalkyl, aminoalkyl,—(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂; COOH, C(O)O-alkyl orC(O)H; wherein at least one of R₁ and R₄ is not hydrogen;R₂ and R₅ are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl,aminoalkyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂; OCH₂Ph,OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkyl or C(O)H;m is an integer between 1-4;i is an integer between 0-5; andn is an integer between 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.In one embodiment, this invention is directed to a compound of formulaXIV:

wherein R₁ and R₄ are independently H, O-alkyl, I, Br, Cl, F, alkyl,haloalkyl, aminoalkyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂,—(CH₂)_(i)N(CH₃)₂, OCH₂Ph, OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkylor C(O)H; wherein at least one of R₁ and R₄ is not hydrogen;R₂ and R₅ are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl,aminoalkyl, OCH₂Ph, OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkyl orC(O)H;m is an integer between 1-4;i is an integer between 0-5; andn is an integer between 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, R₁ of compound of formula XII, XIII and XIV is OCH₃.In another embodiment, R₁ of compound of formula XII, XIII and XIV is4-F. In another embodiment, R₁ of compound of formula XII, XIII and XIVis OCH₃ and m is 3. In another embodiment, R₄ of compound of formulaXII, XIII and XIV is 4-F. In another embodiment, R₄ of compound offormula XII, XIII and XIV is OCH₃. In another embodiment, R₄ of compoundof formula XIV is CH₃. In another embodiment, R₄ of compound of formulaXII, XIII and XIV is 4-Cl. In another embodiment, R₄ of compound offormula XII, XIII and XIV is 4-N(Me)₂. In another embodiment, R₄ ofcompound of formula XII, XIII and XIV is OBn. In another embodiment, R₄of compound of formula XII, XIII and XIV is 4-Br. In another embodiment,R₄ of compound of formula XII, XIII and XIV is 4-CF₃. Non limitingexamples of compounds of formula XIV are selected from:(2-phenyl-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12aa),(4-fluorophenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12af),(2-(4-fluorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ba),(2-(4-methoxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ca), (4-fluorophenyl)(2-(4-methoxyphenyl)-1H-imidazol-4-yl)methanone(12cb), (2-(p-tolyl)-1H-midazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12da), (4-fluorophenyl)(2-(p-tolyl)-1H-imidazol-4-yl)methanone (12 db),(4-Hydroxy-3,5-dimethoxyphenyl)(2-(p-tolyl)-1H-imidazol-4-yl)methanone(12dc),(2-(4-chlorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12fa), (2-(4-chlorophenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12fb),(2-(4-chlorophenyl)-1H-imidazol-4-yl)(4-hydroxy-3,5-dimethoxyphenyl)methanone(12fc),(2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ga);(2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12gb),(2-(3,4-dimethoxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ha),(2-(4-(benzyloxy)phenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12jb),(2-(4-bromophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12la),(2-(4-(Ttrifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12pa).

In one embodiment, this invention is directed to a compound of formulaXIVa:

wherein R₁ and R₄ are independently H, O-alkyl, I, Br, Cl, F, alkyl,haloalkyl, aminoalkyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂,—(CH₂)_(i)N(CH₃)₂, OCH₂Ph, OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkylor C(O)H; wherein at least one of R₁ and R₄ is not hydrogen;R₂ and R₅ are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl,aminoalkyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, OCH₂Ph,OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkyl or C(O)H;R₉ is H, linear or branched, substituted or unsubstituted alkyl,substituted or unsubstituted aryl, CH₂Ph, substituted benzyl, haloalkyl,aminoalkyl, OCH₂Ph, substituted or unsubstituted SO₂-Aryl, substitutedor unsubstituted —(C═O)-Aryl or OH;wherein substitutions are independently selected from the group ofhydrogen (e.g., no substitution at a particular position), hydroxyl, analiphatic straight- or branched-chain C₁ to C₁₀ hydrocarbon, alkoxy,haloalkoxy, aryloxy, nitro, cyano, alkyl-CN, halo (e.g., F, Cl, Br, I),haloalkyl, dihaloalkyl, trihaloalkyl, COOH, C(O)Ph, C(O)-alkyl,C(O)O-alkyl, C(O)H, C(O)NH₂, —OC(O)CF₃, OCH₂Ph, amino, aminoalkyl,alkylamino, mesylamino, dialkylamino, arylamino, amido, NHC(O)-alkyl,urea, alkyl-urea, alkylamido (e.g., acetamide), haloalkylamido,arylamido, aryl, and C₅ to C₇ cycloalkyl, arylalkyl, and combinationsthereof;m is an integer between 1-4;i is an integer between 0-5; andn is an integer between 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, R₉ of compound of formula XIVa is CH₃. In anotherembodiment, R₉ of compound of formula XIVa is CH₂Ph. In anotherembodiment, R₉ of compound of formula XIVa is (SO₂)Ph. In anotherembodiment, R₉ of compound of formula XIVa is (SO₂)-Ph-OCH₃. In anotherembodiment, R₉ of compound of formula XIVa is H. In another embodiment,R₄ of compound of formula XIVa is H. In another embodiment, R₄ ofcompound of formula XIVa is CH₃. In another embodiment, R₄ of compoundof formula XIVa is OCH₃. In another embodiment, R₄ of compound offormula XIVa is OH. In another embodiment, R₄ of compound of formulaXIVa is 4-Cl. In another embodiment, R₄ of compound of formula XIVa is4-N(Me)₂. In another embodiment, R₄ of compound of formula XIVa is OBn.In another embodiment, R₁ of compound of formula XIVa is OCH₃; m is 3and R₂ is H. In another embodiment, R₁ of compound of formula XIVa is F;m is 1 and R₂ is H. Non limiting examples of compounds of formula XIVaare selected from:(4-fluorophenyl)(2-phenyl-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone(11af),(4-fluorophenyl)(2-(4-methoxyphenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone(11cb),(4-fluorophenyl)(1-(phenylsulfonyl)-2-(p-tolyl)-1H-imidazol-4-yl)methanone(11 db),(2-(4-chlorophenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(11fb),(2-(4-(dimethylamino)phenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11ga),(2-(4-(dimethylamino)phenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(11gb),(2-(3,4-dimethoxyphenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11ha),(2-(4-(benzyloxy)phenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(11jb),(2-(4-(dimethylamino)phenyl)-1-((4-methoxyphenyl)sulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12gba),(1-benzyl-2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12daa);(1-methyl-2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12dab);(4-fluorophenyl)(2-(4-methoxyphenyl)-1-methyl-1H-imidazol-4-yl)methanone(12cba).

In one embodiment, this invention is directed to a compound of formulaXV:

wherein R₄ and R₅ are independently H, O-alkyl, I, Br, Cl, F, alkyl,haloalkyl, aminoalkyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂,—(CH₂)_(i)N(CH₃)₂, OCH₂Ph, OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkylor C(O)H;i is an integer between 0-5; andn is an integer between is 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, R₄ of compound of formula XV is H. In anotherembodiment, R₄ of compound of formula XV is F. In another embodiment, R₄of compound of formula XV is Cl In another embodiment, R₄ of compound offormula XV is Br. In another embodiment, R₄ of compound of formula XV isI. In another embodiment, R₄ of compound of formula XV is N(Me)₂. Inanother embodiment, R₄ of compound of formula XV is OBn. In anotherembodiment, R₄ of compound of formula XV is OCH₃. In another embodiment,R₄ of compound of formula XV is CH₃. In another embodiment, R₄ ofcompound of formula XV is CF₃. Non limiting examples of compounds offormula XV are selected from:(2-phenyl-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12aa),(2-(4-fluorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ba),(2-(4-methoxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ca), (2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12da),(3,4,5-trimethoxyphenyl)(2-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)methanone(12ea),(2-(4-chlorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12fa),(2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ga),(2-(3,4-dimethoxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ha),(2-(2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ia),(2-(4-(benzyloxy)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ja),(2-(4-hydroxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ka),(2-(4-bromophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12la),(2-(4-(Ttrifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12pa).

In one embodiment, this invention is directed to a compound of formulaXVI:

wherein R₄ and R₅ are independently H, O-alkyl, I, Br, Cl, F, alkyl,haloalkyl, aminoalkyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂,—(CH₂)_(i)N(CH₃)₂, OCH₂Ph, OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkylor C(O)H;

R₃ is I, Br, Cl, F;

i is an integer between 0-5; andn is an integer between 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, R₃ of compound of formula XVI is halogen. In anotherembodiment, R₃ is F. In another embodiment, R₃ is Cl. In anotherembodiment R₃ is Br. In another embodiment R₃ is I. In anotherembodiment R₄ is H. In another embodiment R₄ is OCH₃. In anotherembodiment R₄ is OCH₃; n is 3 and R₅ is H. In another embodiment R₄ isCH₃. In another embodiment R₄is F. In another embodiment R₄ is Cl. Inanother embodiment R₄ is Br. In another embodiment R₄ is I. In anotherembodiment R₄ is N(Me)₂. In another embodiment R₄ is OBn. In anotherembodiment, R₃ is F; R₅ is hydrogen; n is 1 and R₄ is 4-Cl. In anotherembodiment, R₃ is F; R₅ is hydrogen; n is 1 and R₄ is 4-OCH₃. In anotherembodiment, R₃ is F; R₅ is hydrogen; n is 1 and R₄ is 4-CH₃. In anotherembodiment, R₃ is F; R₅ is hydrogen; n is 1 and R₄ is 4-N(Me)₂. Inanother embodiment, R₃ is F; R₅ is hydrogen; n is 1 and R₄ is 4-OBn. Nonlimiting examples of compounds of formula XVI are selected from:(4-fluorophenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12af),(4-fluorophenyl)(2-(4-methoxyphenyl)-1H-imidazol-4-yl)methanone (12cb),(4-fluorophenyl)(2-(p-tolyl)-1H-imidazol-4-yl)methanone (12 db),4-fluorophenyl)(2-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)methanone(12eb), (2-(4-chlorophenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12fb),(2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12gb),(2-(4-(benzyloxy)phenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12jb).

In one embodiment, this invention is directed to a compound of formulaXVII:

wherein R₄ is H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl,OCH₂Ph, OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkyl or C(O)H;wherein R₁ and R₂ are independently H, O-alkyl, I, Br, Cl, F, alkyl,haloalkyl, aminoalkyl, OCH₂Ph, OH, CN, NO₂, —NHCO-alkyl, COOH,C(O)O-alkyl or C(O)H;andm is an integer between 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.In one embodiment, R₄ of compound of formula XVII is halogen. In anotherembodiment, R₄ is F. In another embodiment, R₄ is Cl. In anotherembodiment R₄ is Br. In another embodiment R₄ is I. In anotherembodiment, R₄ is OCH₃. In another embodiment, R₄ is CH₃. In anotherembodiment, R₄ is N(Me)₂. In another embodiment, R₄ is CF₃. In anotherembodiment, R₄ is OH. In another embodiment, R₄ is OBn. In anotherembodiment, R₁ of compound of formula XVII is halogen. In anotherembodiment, R₁ of compound of formula XVII is F. In another embodiment,R₁ of compound of formula XVII is Cl. In another embodiment, R₁ ofcompound of formula XVII is Br. In another embodiment, R₁ of compound offormula XVII is I. In another embodiment, R₁ of compound of formula XVIIis OCH₃. In another embodiment, R₁ of compound of formula XVII is OCH₃,m is 3 and R₂ is H. In another embodiment, R₁ of compound of formulaXVII is F, m is 1 and R₂ is H. In another embodiment, R₄ is F; R₂ ishydrogen; n is 3 and R₁ is OCH₃. In another embodiment, R₄ is OCH₃; R₂is hydrogen; n is 3 and R₁ is OCH₃. In another embodiment, R₄ is CH₃; R₂is hydrogen; n is 3 and R₁ is OCH₃. In another embodiment, R₄ is Cl; R₂is hydrogen; n is 3 and R₁ is OCH₃. In another embodiment, R₄ is N(Me)₂;R₂ is hydrogen; n is 3 and R₁ is OCH₃. In one embodiment, R₄ of compoundof formula XVII is halogen, R₁ is H and R₂ is halogen. In oneembodiment, R₄ of compound of formula XVII is halogen, R₁ is halogen andR₂ is H. In one embodiment, R₄ of compound of formula XVII is alkoxy, R₁is halogen and R₂ is H. In one embodiment, R₄ of compound of formulaXVII is methoxy, R₁ is halogen and R₂ is H. Non limiting examples ofcompounds of formula XVII are selected from:(2-(4-fluorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ba),(2-(4-methoxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ca), (4-fluorophenyl)(2-(4-methoxyphenyl)-1H-imidazol-4-yl)methanone(12cb), (2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12da), (4-fluorophenyl)(2-(p-tolyl)-1H-imidazol-4-yl)methanone (12 db),(4-Hydroxy-3,5-dimethoxyphenyl)(2-(p-tolyl)-1H-imidazol-4-yl)methanone(12dc),(2-(4-chlorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12fa), (2-(4-chlorophenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12fb),(2-(4-chlorophenyl)-1H-imidazol-4-yl)(3,4,5-trihydroxyphenyl)methanone(13fa),(2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ga),(2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12gb),(2-(4-(benzyloxy)phenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12jb),(2-(4-hydroxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ka),(2-(4-bromophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12la),(2-(4-(Ttrifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12pa).

In another embodiment a compound of formula XVII is represented by thestructure of formula 12fb:

In another embodiment a compound of formula XVII is represented by thestructure of formula 12cb:

In one embodiment, this invention is directed to a compound of formulaXVIII:

wherein

W is C═O, C═S, SO₂ or S═O;

R₄ and R₇ are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl,aminoalkyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, OCH₂Ph,OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkyl or C(O)H;R₅ and R₈ are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl,aminoalkyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, OCH₂Ph,OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkyl or C(O)H;n is an integer between 1-4;i is an integer between 0-5; andq is an integer between 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, W of compound of formula XVIII is C═O. In anotherembodiment, W of compound of formula XVIII is SO₂. In anotherembodiment, R₄ of compound of formula XVIII is H. In another embodiment,R₄ of compound of formula XVIII is NO₂. In another embodiment, R₄ ofcompound of formula XVIII is OBn. In another embodiment, R₇ of compoundof formula XVIII is H. In another embodiment, R₇ of compound of formulaXVIII is OCH₃. In another embodiment, R₇ of compound of formula XVIII isOCH₃ and q is 3. Non limiting examples of compounds of formula XVII areselected from: (4-methoxyphenyl)(2-phenyl-1H-imidazol-1-yl)methanone(12aba), (2-phenyl-1H-imidazol-1-yl)(3,4,5-trimethoxyphenyl)methanone(12aaa), 2-phenyl-1-(phenylsulfonyl)-1H-imidazole (10a),2-(4-nitrophenyl)-1-(phenylsulfonyl)-1H-imidazole (10x),2-(4-(benzyloxy)phenyl)-1-(phenylsulfonyl)-1H-imidazole (10j).

In one embodiment, this invention is directed to a compound of formulaXIX:

wherein

W is C═O, C═S, SO₂, S═O;

R₁, R₄ and R₇ are independently H, O-alkyl, I, Br, Cl, F, alkyl,haloalkyl, aminoalkyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂,—(CH₂)_(i)N(CH₃)₂, OCH₂Ph, OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkylor C(O)H;R₂, R₅ and R₈ are independently H, O-alkyl, I, Br, Cl, F, alkyl,haloalkyl, aminoalkyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂,—(CH₂)_(i)N(CH₃)₂, OCH₂Ph, OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkylor C(O)H;m is an integer between 1-4;n is an integer between 1-4;i is an integer between 0-5; andq is 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, R₁, R₄ and R₇ of formula XIX are independently H. Inanother embodiment, R₁, R₄ and R₇ of formula XIX are independentlyO-alkyl. In another embodiment, R₁, R₄ and R₇ of formula XIX areindependently halogen. In another embodiment, R₁, R₄ and R₇ of formulaXIX are independently CN. In another embodiment, R₁, R₄ and R₇ offormula XIX are independently OH. In another embodiment, R₁, R₄ and R₇of formula XIX are independently alkyl. In another embodiment, R₁, R₄and R₇ of formula XIX are independently OCH₂Ph. In one embodiment R₂, R₅and R₈ of formula XIX are independently H. In another embodiment, R₂, R₅and R₈ of formula XIX are independently O-alkyl. In another embodiment,R₂, R₅ and R₈ of formula XIX are independently halogen. In anotherembodiment, R₂, R₅ and R₈ of formula XIX are independently CN. Inanother embodiment, R₂, R₅ and R₈ of formula XIX are independently OH.In another embodiment, R₂, R₅ and R₈ of formula XIX are independentlyalkyl. In another embodiment, R₂, R₅ and R₈ of formula XIX areindependently OCH₂Ph. In another embodiment, R₅, R₂ and R₈ of formulaXIX are H, R₄ is 4-N(Me)₂, R₁ is OCH₃, m is 3 and R₇ is OCH₃. In anotherembodiment, R₅, R₂, R₇ and R₈ of formula XIX are H, R₄ is 4-Br, R₁ isOCH₃, and m is 3. In another embodiment W is SO₂. In another embodimentW is C═O. In another embodiment W is C═S. In another embodiment W isS═O, Non limiting examples of compounds of formula XIX are selectedfrom:(2-(4-(dimethylamino)phenyl)-1-(4-methoxyphenyl)sulfonyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11gaa);(2-(4-bromophenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11la),(4-fluorophenyl)(2-(4-methoxyphenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone(11cb),(2-(4-chlorophenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(11fb),(4-fluorophenyl)(2-phenyl-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone(11af),(4-fluorophenyl)(1-(phenylsulfonyl)-2-(p-tolyl)-1H-imidazol-4-yl)methanone(11db),(2-(4-(dimethylamino)phenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11ga),(2-(4-(dimethylamino)phenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(11gb),(2-(3,4-dimethoxyphenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11ha),(2-(4-(benzyloxy)phenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(11jb),(2-(4-(dimethylamino)phenyl)-1-((4-methoxyphenyl)sulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12gba).

In another embodiment a compound of formula XIX is represented by thestructure of formula 11cb:

In another embodiment a compound of formula XIX is represented by thestructure of formula 11fb:

In one embodiment, this invention is directed to a compound of formulaXX:

whereinR₄ is H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl,—(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, OCH₂Ph, OH, CN, NO₂,—NHCO-alkyl, COOH, C(O)O-alkyl or C(O)H; andi is an integer between 0-5;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, R₄ of compound of formula XX is H. In anotherembodiment, R₄ of compound of formula XX is halogen. In anotherembodiment, R₄ is F. In another embodiment, R₄ is Cl. In anotherembodiment R₄ is Br. In another embodiment R₄ is I. In anotherembodiment, R₄ is alkyl. In another embodiment, R₄ is methyl. Nonlimiting examples of compounds of formula XX are selected from:(2-phenyl-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12aa),(2-(4-fluorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ba),(2-(4-methoxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ca), (2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12da),(3,4,5-trimethoxyphenyl)(2-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)methanone(12ea),(2-(4-chlorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12fa),(2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ga),(2-(3,4-dimethoxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ha),(2-(2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ia),(2-(4-(benzyloxy)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ja),(2-(4-hydroxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ka),(2-(4-bromophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12la),(2-(4-(Ttrifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12pa).

In another embodiment a compound of formula XX is represented by thestructure of formula 12da:

In another embodiment a compound of formula XX is represented by thestructure of formula 12fa:

In one embodiment, this invention is directed to a compound of formulaXXI:

whereinA is indolyl;

Q is NH, O or S;

R₁ and R₂ are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl,aminoalkyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, OCH₂Ph,OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkyl or C(O)H; andi is an integer between 0-5;wherein said A is optionally substituted by substituted or unsubstitutedO-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂,hydroxyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃,substituted or unsubstituted —SO₂-aryl, substituted or unsubstitutedC₁-C₅ linear or branched alkyl, substituted or unsubstituted haloalkyl,substituted or unsubstituted alkylamino, substituted or unsubstitutedaminoalkyl, —OCH₂Ph, substituted or unsubstituted —NHCO-alkyl, COOH,substituted or unsubstituted —C(O)Ph, substituted or unsubstitutedC(O)O-alkyl, C(O)H, —C(O)NH₂, NO₂ or combination thereof;i is an integer between 0-5; andm is an integer between 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, R₁ of compound of formula XXI is OCH₃; m is 3 and R₂is hydrogen. In another embodiment, R₁ is F; m is 1 and R₂ is hydrogen.In one embodiment, Q of formula XXI is O. In another embodiment Q offormula XXI is NH. In another embodiment, Q of formula XXI is S.

In one embodiment, A ring of compound of formula XXI is substituted5-indolyl. In another embodiment the substitution is —(C═O)-Aryl. Inanother embodiment, the aryl is 3,4,5-(OCH₃)₃-Ph.

In another embodiment, A ring of compound of formula XXI is 3-indolyl.In another embodiment, A ring of compound of formula XXI is 5-indolyl.In another embodiment, A ring of compound of formula XXI is 2-indolyl.Non limiting examples of compounds of formula XXI are selected from:(5-(4-(3,4,5-trimethoxybenzoyl)-1H-imidazol-2-yl)-1H-indol-2-yl)(3,4,5-trimethoxyphenyl)methanone(15xaa);(1-(phenylsulfonyl)-2-(1-(phenylsulfonyl)-2-(3,4,5-trimethoxybenzoyl)-1H-indol-5-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(16xaa);2-(1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(17ya); (2-(1H-indol-2-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(62a); and(2-(1H-indol-5-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (66a).

In one embodiment, this invention is directed to a compound of formulaXXIa:

wherein

W is C═O, C═S, SO₂, S═O;

A is indolyl;R₁ and R₂ are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl,aminoalkyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, OCH₂Ph,OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkyl or C(O)H;R₇, and R₈ are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl,aminoalkyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, OCH₂Ph,OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkyl or C(O)H;wherein said A is optionally substituted by substituted or unsubstitutedO-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂,hydroxyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃,substituted or unsubstituted —SO₂-aryl, substituted or unsubstitutedC₁-C₅ linear or branched alkyl, substituted or unsubstituted haloalkyl,substituted or unsubstituted alkylamino, substituted or unsubstitutedaminoalkyl, —OCH₂Ph, substituted or unsubstituted —NHCO-alkyl, COOH,substituted or unsubstituted —C(O)Ph, substituted or unsubstitutedC(O)O-alkyl, C(O)H, —C(O)NH₂, NO₂ or combination thereof;i is an integer between 0-5; andm is an integer between 1-4;q is an integer between 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, R₁ of compound of formula XXIa is OCH₃; m is 3 and R₂is hydrogen. In another embodiment, R₁ is F; m is 1 and R₂ is hydrogen.In another embodiment, A ring of compound of formula XXIa is substituted5-indolyl. In another embodiment, A ring of compound of formula XXIa is3-indolyl. Non limiting examples of compounds of formula XXIa areselected from:(1-(phenylsulfonyl)-2-(1-(phenylsulfonyl)-2-(3,4,5-trimethoxybenzoyl)-1H-indol-5-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(16xaa);(1-(phenylsulfonyl)-2-(1-(phenylsulfonyl)-1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(17yaa).

In one embodiment, this invention is directed to a compound of formulaXXII:

whereinA is indolyl;wherein said A is optionally substituted by substituted or unsubstitutedO-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂,hydroxyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃,substituted or unsubstituted —SO₂-aryl, substituted or unsubstitutedC₁-C₅ linear or branched alkyl, substituted or unsubstituted haloalkyl,substituted or unsubstituted alkylamino, substituted or unsubstitutedaminoalkyl, —OCH₂Ph, substituted or unsubstituted —NHCO-alkyl, COOH,substituted or unsubstituted —C(O)Ph, substituted or unsubstitutedC(O)O-alkyl, C(O)H, —C(O)NH₂, NO₂ or combination thereof;i is an integer between 0-5;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, A ring of compound of formula XXII is substituted5-indolyl. In another embodiment the substitution is —(C═O)-Aryl. Inanother embodiment, the aryl is 3,4,5-(OCH₃)₃-Ph.

In another embodiment, A ring of compound of formula XXII is 3-indolyl.Non limiting examples of compounds of formula XXII are selected from:(5-(4-(3,4,5-trimethoxybenzoyl)-1H-imidazol-2-yl)-1H-indol-2-yl)(3,4,5-trimethoxyphenyl)methanone(15xaa);2-(1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(17ya),

In another embodiment a compound of formula XXI or XXII is representedby the structure of formula 17ya:

In one embodiment, Q of compound of formula XII is H and P

In another embodiment, P of compound of formula XII is H and Q is

In another embodiment, P of compound of formula XII is

and Q is SO₂-Ph. In one embodiment Q of compound of formula XII is H andP is

wherein W is C═O. In another embodiment W of compound of formula XII,XVIII, XIX, or XXIa is C═O. In another embodiment, W of compound offormula XII, XVIII, XIX, or XXIa is SO₂. In another embodiment, W ofcompound of formula XII, XVIII, XIX, or XXIa is C═S. In anotherembodiment, W of compound of formula XII, XVIII, XIX, or XXIa is S═O.

In one embodiment, Z of compound of formula XIII is oxygen. In anotherembodiment, Z of compound of formula XIII is sulfur.

In one embodiment, R₅ of compound of formula XII-XVI, XVIII, or XIX ishydrogen, n is 1 and R₄ is in the para position.

In one embodiment, R₄ of compound of formula XII-XX is alkyl. In anotherembodiment, R₄ of compound of formula XII-XX is H. In anotherembodiment, R₄ of compound of formula XII-XX is methyl (CH₃). In anotherembodiment, R₄ of compound of formula XII-XX is O-alkyl. In anotherembodiment, R₄ of compound of formula XII-XIX is OCH₃. In anotherembodiment, R₄ of compound of formula XII-XX is I. In anotherembodiment, R₄ of compound of formula XII-XX is Br. In anotherembodiment, R₄ of compound of formula XII-XX is F. In anotherembodiment, R₄ of compound of formula XII-XX is Cl. In anotherembodiment, R₄ of compound of formula XII-XX is N(Me)₂. In anotherembodiment, R₄ of compound of formula XII-XX is OBn. In anotherembodiment, R₄ of compound of formula XII-XX is OH. In anotherembodiment, R₄ of compound of formula XII-XX is CF₃.

In one embodiment, R₂ of compound of formula XII, XIII, XIV, XIVa, XVII,XIX, XXI or XXIa is hydrogen; R₁ is OCH₃ and m is 3. In anotherembodiment, R₂ of compound of formula XII, XIII, XIV, XIVa, XVII, XIX,XXI or XXIa is hydrogen; m is 1 and R₁ is in the para position. Inanother embodiment, R₂ of compound of formula XII, XIII, XIV, XIVa,XVII, XIX, XXI or XXIa is hydrogen; m is 1 and R₁ is I. In anotherembodiment, R₂ of compound of formula XII, XIII, XIV, XIVa, XVII, XIX,XXI or XXIa is hydrogen; m is 1 and R₁ is Br. In another embodiment, R₂of compound of formula XII, XIII, XIV, XIVa, XVII, XIX, XXI or XXIa ishydrogen; m is 1 and R₁ is F. In another embodiment, R₂ of compound offormula XII, XIII, XIV, XIVa, XVII, XIX, XXI or XXIa is hydrogen; m is 1and R₁ is Cl. In another embodiment, R₁ of compound of formula XII,XIII, XIV, XIVa, XVII, XIX, XXI or XXIa is I. In another embodiment, R₁of compound of formula XII, XIII, XIV, XIVa, XVII, XIX, XXI or XXIa isBr. In another embodiment, R₁ of compound of formula XII, XIII, XIV,XIVa, XVII, XIX, XXI or XXIa is Cl. In another embodiment, R₁ ofcompound of formula XII, XIII, XIV, XIVa, XVII, XIX, XXI or XXIa is F.

In one embodiment Q of compound of formula XII is H and P is

wherein W is C═O, Non-limiting examples of compounds of formula XII-XVIIand XX-XXII are selected from(2-phenyl-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12aa);(4-methoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ab);(3-methoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ac);(3,5-dimethoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ad);(3,4-dimethoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ae);(4-fluorophenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12af);(3-fluorophenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ag);(2-phenyl-1H-imidazol-4-yl)(p-tolyl)methanone (12ah);(2-phenyl-1H-imidazol-4-yl)(m-tolyl)methanone (12ai);(2-(4-fluorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ba);(2-(4-methoxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ca); (4-fluorophenyl)(2-(4-methoxyphenyl)-1H-imidazol-4-yl)methanone(12cb); (2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12da); (4-fluorophenyl)(2-(p-tolyl)-1H-imidazol-4-yl)methanone (12 db);(4-fluorophenyl)(2-(p-tolyl)-1H-imidazol-4-yl)methanone hydrochloride(12 db-HCl);(4-Hydroxy-3,5-dimethoxyphenyl)(2-(p-tolyl)-1H-imidazol-4-yl)methanone(12dc);(3,4,5-trimethoxyphenyl)(2-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)methanone(12ea);(4-fluorophenyl)(2-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)methanone(12eb);(2-(4-chlorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12fa); (2-(4-chlorophenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12fb);(2-(4-chlorophenyl)-1H-imidazol-4-yl)(4-hydroxy-3,5-dimethoxyphenyl)methanone(12fc);(2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ga);(2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12gb);(2-(3,4-dimethoxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ha);(2-(3,4-dimethoxyphenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12hb);(2-(2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ia);(4-fluorophenyl)(2-(2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)methanone(12ib);(2-(4-(benzyloxy)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ja);(2-(4-(benzyloxy)phenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12jb);(2-(4-hydroxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ka); (2-(4-(hydroxyphenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12 kb);(2-(4-bromophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12la);(2-(4-(Ttrifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12pa);(3,4,5-trihydroxyphenyl)(2-(3,4,5-trihydroxyphenyl)-1H-imidazol-4-yl)methanone(13ea);(2-(4-chlorophenyl)-1H-imidazol-4-yl)(3,4,5-trihydroxyphenyl)methanone(13fa); and2-(3,4-dihydroxyphenyl)-1H-imidazol-4-yl)(3,4,5-trihydroxyphenyl)methanone(13ha).

In one embodiment, P of compound of formula XII is

and Q is SO₂-Ph. Non-limiting examples of compound of formula XIIwherein P of compound of formula XII is

and Q is SO₂-Ph are selected from(4-methoxyphenyl)(2-phenyl-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone(11ab);(3-methoxyphenyl)(2-phenyl-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone(11ac); (2-phenyl-1-(phenylsulfonyl)-1H-imidazol-4-yl(p-tolyl)methanone(11ah);(4-fluorophenyl)(2-phenyl-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone(11af);(3-fluorophenyl)(2-phenyl-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone(11ag);(4-fluorophenyl)(2-(4-methoxyphenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone(11cb);(1-(phenylsulfonyl)-2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11da);(4-fluorophenyl)(1-(phenylsulfonyl)-2-(p-tolyl)-1H-imidazol-4-yl)methanone(11 db);(1-(phenylsulfonyl)-2-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11ea);(4-fluorophenyl)(1-(phenylsulfonyl)-2-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)methanone(11eb);(2-(4-chlorophenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(11ha);(2-(4-(dimethylamino)phenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11ga);(2-(4-(dimethylamino)phenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(11gb);(2-(3,4-dimethoxyphenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11ha);(2-(3,4-dimethoxyphenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(11hb);(1-(phenylsulfonyl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11ia);(1-(phenylsulfonyl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(11ib); and(2-(4-(benzyloxy)phenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(11jb);(2-(4-bromophenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11la);(1-(phenylsulfonyl)-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11pa).

In one embodiment, R₄ and R₅ of compounds of formula XIII-XVI arehydrogens. Non-limiting examples of compounds of formula XIII-XVIwherein R₄ and R₅ are hydrogens are selected from(2-phenyl-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12aa);(4-methoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ab);(3-methoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ac);(3,5-dimethoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ad);(3,4-dimethoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ae);(4-fluorophenyl)(2-phenyl-1H-imidazol-4-yl)methanone (120);(3-fluorophenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ag);(2-phenyl-1H-imidazol-4-yl)(p-tolyl)methanone (12ah); and(2-phenyl-1H-imidazol-4-yl)(m-tolyl)methanone (12ai).

In one embodiment, P of compound of formula XII is H and Q is In anotherembodiment W is C═O. In another embodiment, W of compound of formulaXVIII is C═O. Non-limiting examples of compound of formula XVIII whereinW is C═O are selected from(4-methoxyphenyl)(2-phenyl-1H-imidazol-1-yl)methanone (12aba) and(2-phenyl-1H-imidazol-1-yl)(3,4,5-trimethoxyphenyl)methanone (12aaa).

In another embodiment, W of compound of formula XVIII is SO₂.Non-limiting examples of compound of formula XVIII wherein W is SO₂ areselected from 2-phenyl-1-(phenylsulfonyl)-1H-imidazole (10a);2-(4-nitrophenyl)-1-(phenylsulfonyl)-1H-imidazole (10x) and2-(4-(benzyloxy)phenyl)-1-(phenylsulfonyl)-1H-imidazole (10j).

As used herein, “single-, fused- or multiple-ring, aryl or(hetero)cyclic ring systems” can be any such ring, including but notlimited to phenyl, biphenyl, triphenyl, naphthyl, cycloalkyl,cycloalkenyl, cyclodienyl, fluorene, adamantane, etc.

“Saturated or unsaturated N-heterocycles” can be any such N-containingheterocycle, including but not limited to aza- and diaza-cycloalkylssuch as aziridinyl, azetidinyl, diazatidinyl, pyrrolidinyl, piperidinyl,piperazinyl, and azocanyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl,pyrrolizinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl,indazolyl, quinolizinyl, cinnolinyl, quinoxolinyl, phthalazinyl,naphthyridinyl, quinoxalinyl, etc.

“Saturated or unsaturated O-Heterocycles” can be any such O-containingheterocycle including but not limited to oxiranyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, furanyl, pyrylium,benzofuranyl, benzodioxolyl, etc.

“Saturated or unsaturated S-heterocycles” can be any such S-containingheterocycle, including but not limited to thiranyl, thietanyl,tetrahydrothiophene-yl, dithiolanyl, tetrahydrothiopyranyl,thiophene-yl, thiepinyl, thianaphthenyl, etc.

“Saturated or unsaturated mixed heterocycles” can be any heterocyclecontaining two or more S—, N—, or O-heteroatoms, including but notlimited to oxathiolanyl, morpholinyl, thioxanyl, thiazolyl,isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiaziolyl, etc.

As used herein, “aliphatic straight- or branched-chain hydrocarbon”refers to both alkylene groups that contain a single carbon and up to adefined upper limit, as well as alkenyl groups and alkynyl groups thatcontain two carbons up to the upper limit, whether the carbons arepresent in a single chain or a branched chain. Unless specificallyidentified, a hydrocarbon can include up to about 30 carbons, or up toabout 20 hydrocarbons, or up to about 10 hydrocarbons. Alkenyl andalkynyl groups can be mono-unsaturated or polyunsaturated. In anotherembodiment, an alkyl includes C₁-C₆ carbons. In another embodiment, analkyl includes C₁-C₈ carbons. In another embodiment, an alkyl includesC₁-C₁₀ carbons. In another embodiment, an alkyl is a C₁-C₁₂ carbons. Inanother embodiment, an alkyl is a C₁-C₅ carbons.

As used herein, the term “alkyl” can be any straight- or branched-chainalkyl group containing up to about 30 carbons unless otherwisespecified. In another embodiment, an alkyl includes C₁-C₆ carbons. Inanother embodiment, an alkyl includes C₁-C₈ carbons. In anotherembodiment, an alkyl includes C₁-C₁₀ carbons. In another embodiment, analkyl is a C₁-C₁₂ carbons. In another embodiment, an alkyl is a C₁-C₂₀carbons. In another embodiment, cyclic alkyl group has 3-8 carbons. Inanother embodiment, branched alkyl is an alkyl substituted by alkyl sidechains of 1 to 5 carbons.

The alkyl group can be a sole substituent or it can be a component of alarger substituent, such as in an alkoxy, haloalkyl, arylalkyl,alkylamino, dialkylamino, alkylamido, allylurea, etc. Preferred alkylgroups are methyl, ethyl, and propyl, and thus halomethyl, dihalomethyl,trihalomethyl, haloethyl, dihaloethyl, dihaloethyl, halopropyl,dihalopropyl, trihalopropyl, methoxy, ethoxy, propoxy, arylmethyl,arylmethyl, arylpropyl, methylamino, ethylamino, propylamino,dimethylamino, diethylamino, methylamido, acetamido, propylamido,halomethylamido, haloethylamido, halopropylamido, methyl-urea,ethyl-urea, propyl-urea, etc.

As used herein, the term “aryl” refers to any aromatic ring that isdirectly bonded to another group. The aryl group can be a solesubstituent, or the aryl group can be a component of a largersubstituent, such as in an arylalkyl, arylamino, arylamido, etc.Exemplary aryl groups include, without limitation, phenyl, tolyl, xylyl,furanyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl,triazinyl, thiazolyl, oxazolyl, isooxazolyl, pyrazolyl, imidazolyl,thiophene-yl, pyrrolyl, phenylmethyl, phenylethyl, phenylamino,phenylamido, etc.

As used herein, the term “aminoalkyl” refers to an amine groupsubstituted by an alkyl group as defined above. Aminoalkyl refers tomonoalkylamine, dialkylamine or trialkylamine. Nonlimiting examples ofaminoalkyl groups are —N(Me)₂, —NHMe, —NH₃.

A “haloalkyl” group refers, in another embodiment, to an alkyl group asdefined above, which is substituted by one or more halogen atoms, e.g.by F, Cl, Br or I. Nonlimiting examples of haloalkyl groups are CF₃,CF₂CF₃, CH₂CF₃.

In one embodiment, this invention provides a compound of this inventionor its isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, tautomer, hydrate, N-oxide, polymorph, orcrystal or combinations thereof. In one embodiment, this inventionprovides an isomer of the compound of this invention. In anotherembodiment, this invention provides a metabolite of the compound of thisinvention. In another embodiment, this invention provides apharmaceutically acceptable salt of the compound of this invention. Inanother embodiment, this invention provides a pharmaceutical product ofthe compound of this invention. In another embodiment, this inventionprovides a tautomer of the compound of this invention. In anotherembodiment, this invention provides a hydrate of the compound of thisinvention. In another embodiment, this invention provides an N-oxide ofthe compound of this invention. In another embodiment, this inventionprovides a polymorph of the compound of this invention. In anotherembodiment, this invention provides a crystal of the compound of thisinvention. In another embodiment, this invention provides compositioncomprising a compound of this invention, as described herein, or, inanother embodiment, a combination of an isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, tautomer,hydrate, N-oxide, polymorph, or crystal of the compound of thisinvention.

In one embodiment, the term “isomer” includes, but is not limited to,optical isomers and analogs, structural isomers and analogs,conformational isomers and analogs, and the like.

In one embodiment, the compounds of this invention are the pure(E)-isomers. In another embodiment, the compounds of this invention arethe pure (Z)-isomers. In another embodiment, the compounds of thisinvention are a mixture of the (E) and the (Z) isomers. In oneembodiment, the compounds of this invention are the pure (R)-isomers. Inanother embodiment, the compounds of this invention are the pure(S)-isomers. In another embodiment, the compounds of this invention area mixture of the (R) and the (S) isomers.

The compounds of the present invention can also be present in the formof a racemic mixture, containing substantially equivalent amounts ofstereoisomers. In another embodiment, the compounds of the presentinvention can be prepared or otherwise isolated, using known procedures,to obtain a stereoisomer substantially free of its correspondingstereoisomer (i.e., substantially pure). By substantially pure, it isintended that a stereoisomer is at least about 95% pure, more preferablyat least about 98% pure, most preferably at least about 99% pure.

Compounds of the present invention can also be in the form of a hydrate,which means that the compound further includes a stoichiometric ornon-stoichiometric amount of water bound by non-covalent intermolecularforces.

Compounds of the present invention may exist in the form of one or moreof the possible tautomers and depending on the particular conditions itmay be possible to separate some or all of the tautomers into individualand distinct entities. It is to be understood that all of the possibletautomers, including all additional enol and keto tautomers and/orisomers are hereby covered. For example the following tautomers, but notlimited to these, are included.

Tautomerization of the imidazole ring

The invention includes “pharmaceutically acceptable salts” of thecompounds of this invention, which may be produced, by reaction of acompound of this invention with an acid or base. Certain compounds,particularly those possessing acid or basic groups, can also be in theform of a salt, preferably a pharmaceutically acceptable salt. The term“pharmaceutically acceptable salt” refers to those salts that retain thebiological effectiveness and properties of the free bases or free acids,which are not biologically or otherwise undesirable. The salts areformed with inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid and the like, and organicacids such as acetic acid, propionic acid, glycolic acid, pyruvic acid,oxylic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, N-acetylcysteine and the like. Other salts are known tothose of skill in the art and can readily be adapted for use inaccordance with the present invention.

Suitable pharmaceutically-acceptable salts of amines of compounds thecompounds of this invention may be prepared from an inorganic acid orfrom an organic acid. In one embodiment, examples of inorganic salts ofamines are bisulfates, borates, bromides, chlorides, hemisulfates,hydrobromates, hydrochlorides, 2-hydroxyethylsulfonates(hydroxyethanesulfonates), iodates, iodides, isothionates, nitrates,persulfates, phosphate, sulfates, sulfamates, sulfanilates, sulfonicacids (alkylsulfonates, arylsulfonates, halogen substitutedalkylsulfonates, halogen substituted arylsulfonates), sulfonates andthiocyanates.

In one embodiment, examples of organic salts of amines may be selectedfrom aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, examples of which areacetates, arginines, aspartates, ascorbates, adipates, anthranilates,allegiants, alkane carboxylates, substituted alkane carboxylates,alginates, benzenesulfonates, benzoates, bisulfates, butyrates,bicarbonates, bitartrates, citrates, camphorates, camphorsulfonates,cyclohexylsulfamates, cyclopentanepropionates, calcium edetates,camsylates, carbonates, clavulanates, cinnamates, dicarboxylates,digluconates, dodecylsulfonates, dihydrochlorides, decanoates,enanthuates, ethanesulfonates, edetates, edisylates, estolates,esylates, fumarates, formates, fluorides, galacturonates gluconates,glutamates, glycolates, glucorate, glucoheptanoates, glycerophosphates,gluceptates, glycollylarsanilates, glutarates, glutamate, heptanoates,hexanoates, hydroxymaleates, hydroxycarboxylic acids, hexylresorcinates,hydroxybenzoates, hydroxynaphthoates, hydrofluorates, lactates,lactobionates, laurates, malates, maleates,methylenebis(beta-oxynaphthoate), malonates, mandates, mesylates,methane sulfonates, methylbromides, methylnitrates, methylsulfonates,monopotassium maleates, mutates, monocarboxylates,naphthalenesulfonates, 2-naphthalenesulfonates, nictitates, nitrates,napsylates, N-methylglucamines, oxalates, octanoates, oleates, pamoates,phenylacetates, picrates, phenylbenzoates, pivalates, propionates,phthalates, phenylacetate, pectinates, phenylpropionates, palmitates,pantothenates, polygalacturates, pyruvates, quinates, salicylates,succinates, stearates, sulfanilate, subacetates, tartrates,theophyllineacetates, p-toluenesulfonates (tosylates),trifluoroacetates, terephthalates, tannates, teoclates, trihaloacetates,triethiodide, tricarboxylates, undecanoates and valerates.

In one embodiment, examples of inorganic salts of carboxylic acids orhydroxyls may be selected from ammonium, alkali metals to includelithium, sodium, potassium, cesium; alkaline earth metals to includecalcium, magnesium, aluminium; zinc, barium, cholines, quaternaryammoniums.

In another embodiment, examples of organic salts of carboxylic acids orhydroxyl may be selected from arginine, organic amines to includealiphatic organic amines, alicyclic organic amines, aromatic organicamines, benzathines, t-butylamines, benethamines(N-benzylphenethylamine), dicyclohexylamines, dimethylamines,diethanolamines, ethanolamines, ethylenediamines, hydrabamines,imidazoles, lysines, methylamines, meglamines, N-methyl-D-glucamines,N,N′-dibenzylethylenediamines, nicotinamides, organic amines,ornithines, pyridines, picolies, piperazines, procain,tris(hydroxymethyl)methylamines, triethylamines, triethanolamines,trimethylamines, tromethamines and ureas.

In one embodiment, the salts may be formed by conventional means, suchas by reacting the free base or free acid form of the product with oneor more equivalents of the appropriate acid or base in a solvent ormedium in which the salt is insoluble or in a solvent such as water,which is removed in vacuo or by freeze drying or by exchanging the ionsof a existing salt for another ion or suitable ion-exchange resin.

In some embodiments, this invention provides a process for thepreparation of the compounds of this invention. In one embodiment, thearyl-imidazole is prepared by reacting an appropriately substitutedbenzaldehyde with ethylenediamine to construct the imidazoline ring,followed by oxidation of the imidazoline by an oxidizing agent to thecorresponding imidazole. In another embodiment the oxidizing agent isdiacetoxyiodobenzene, bromotrichloromethane and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), carbon-O₂ system orpalladium-carbon system. In another embodiment, the aryl-imidazole isprepared by reacting an appropriately substituted benzaldehyde withethylene diamine in the presence of iodine and potassium carbonate inorder to construct the imidazoline ring, followed by oxidation of theimidazoline ring catalyzed by diacetoxyiodobenzene,bromotrichloromethane and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),carbon-O₂ system or palladium-carbon system to the correspondingimidazole. In another embodiment, the aryl-imidazole is prepared byreacting an appropriately substituted benzaldehyde with ethylene diaminein the presence of iodine and potassium carbonate in order to constructthe imidazoline ring, followed by oxidation of the imidazoline ringcatalyzed by diacetoxyiodobenzene to the corresponding imidazole. Inanother embodiment, the aryl-imidazole is prepared by reacting anappropriately substituted benzaldehyde with ethylene diamine in thepresence of iodine and potassium carbonate in order to construct theimidazoline ring, followed by oxidation of the imidazoline ringcatalyzed by bromotrichloromethane and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to the corresponding imidazole.In one embodiment, the aryl-imidazole is prepared by reacting theappropriate benzaldehyde in ethanol with oxalaldehyde and ammoniahydroxide to construct the imidazole ring system.

In one embodiment an aryl-benzoyl-imidazole compound of this inventionis prepared by protecting the aryl-imidazole followed by coupling withan appropriately substituted benzoyl chloride, followed by removing theprotecting group. In another embodiment, the protecting group is aphenyl sulfonyl group, phthalimide, di-tert-butyl dicarbonate (Boc),fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), ormonomethoxytrityl (MMT). In another embodiment, the aryl-imidazole isprotected with phenyl sulfonyl to yield the N-sulfonyl protectedaryl-imidazole. In another embodiment, the protected aryl-imidazolecompound is prepared by reacting the aryl-imidazole with phenylsulfonylchloride and sodium hydride in THF. In another embodiment, the protectedaryl-imidazole is prepared according to FIGS. 7 and 8.

In one embodiment, the protected aryl-imidazole is coupled with anappropriately substituted benzoyl chloride to obtain a protectedaryl-benzoyl imidazole. In another embodiment, aryl-imidazole is coupledwith an appropriately substituted benzoyl chloride in the presence oftert-butyl lithium to obtain aryl-phenylsulfonyl(2-aryl-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone. In anotherembodiment, the (2-aryl-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone isprepared according to FIGS. 7 and 8 steps e and c, respectively.

In one embodiment, an aryl-benzoyl-imidazole is prepared by removing theprotecting group of the aryl-benzoyl-imidazole. In another embodiment,the removal of the protecting group depends on the protecting group usedand can be removed by known conditions which are known in the art. Inanother embodiment, the phenyl sulfonyl protecting group is removed bytetrabutylammonium fluoride in THF. In another embodiment,phenylsulfonyl is removed according to FIGS. 7 and 8.

In one embodiment, compounds of formula I, Ia, II, III, V and XI areprepared according to FIG. 1. In another embodiment, compounds offormula I, Ia, II, III, V, VI, VII and XI are prepared according to FIG.2. In another embodiment, compounds of formula I, Ia, II, III, V and VIare prepared according to FIG. 3. In another embodiment, compounds offormula I, Ia, II, III, V and VI are prepared according to FIG. 4. Inanother embodiment, compounds of formula I, Ia, II, III, IV, IVa, V, VIand XI are prepared according to FIG. 5. In another embodiment,compounds of formula I, Ia, II, III, VIII and XI are prepared accordingto FIG. 6.

In one embodiment, compounds of formula XII and XVIII are preparedaccording to FIG. 9. In another embodiment, compounds of formula XII,XIII, XIV, XIVa, XV, XVI, XVII, XIX and XX are prepared according toFIG. 10. In another embodiment, compounds of formula XIVa and XIX areprepared according to FIG. 11. In another embodiment, compounds offormula I, Ia, IV, IVa, XI, XXI, XXIa and XXII are prepared according toFIG. 12. In another embodiment, compounds of formula I, Ia, IV, IVa, XI,XIb, XXI, XXIa and XXII are prepared according to FIG. 13. In anotherembodiment, compounds of formula I, Ia, II, III, V, XI, XII, XIII, XIV,XV, XVII, XIX and XX are prepared according to FIG. 14. In anotherembodiment, compounds of formula I, Ia, II, IV, IVa, XI and XIc, areprepared according to FIG. 15.

In one embodiment, compounds of formula IX and IXa are preparedaccording to FIG. 16.

Pharmaceutical Composition

Another aspect of the present invention relates to a pharmaceuticalcomposition including a pharmaceutically acceptable carrier and acompound according to the aspects of the present invention. Thepharmaceutical composition can contain one or more of theabove-identified compounds of the present invention. Typically, thepharmaceutical composition of the present invention will include acompound of the present invention or its pharmaceutically acceptablesalt, as well as a pharmaceutically acceptable carrier. The term“pharmaceutically acceptable carrier” refers to any suitable adjuvants,carriers, excipients, or stabilizers, and can be in solid or liquid formsuch as, tablets, capsules, powders, solutions, suspensions, oremulsions.

Typically, the composition will contain from about 0.01 to 99 percent,preferably from about 20 to 75 percent of active compound(s), togetherwith the adjuvants, carriers and/or excipients. While individual needsmay vary, determination of optimal ranges of effective amounts of eachcomponent is within the skill of the art. Typical dosages comprise about0.01 to about 100 mg/kg body wt. The preferred dosages comprise about0.1 to about 100 mg/kg body wt. The most preferred dosages compriseabout 1 to about 100 mg/kg body wt. Treatment regimen for theadministration of the compounds of the present invention can also bedetermined readily by those with ordinary skill in art. That is, thefrequency of administration and size of the dose can be established byroutine optimization, preferably while minimizing any side effects.

The solid unit dosage forms can be of the conventional type. The solidform can be a capsule and the like, such as an ordinary gelatin typecontaining the compounds of the present invention and a carrier, forexample, lubricants and inert fillers such as, lactose, sucrose, orcornstarch. In another embodiment, these compounds are tabulated withconventional tablet bases such as lactose, sucrose, or cornstarch incombination with binders like acacia, cornstarch, or gelatin,disintegrating agents, such as cornstarch, potato starch, or alginicacid, and a lubricant, like stearic acid or magnesium stearate.

The tablets, capsules, and the like can also contain a binder such asgum tragacanth, acacia, corn starch, or gelatin; excipients such asdicalcium phosphate; a disintegrating agent such as corn starch, potatostarch, alginic acid; a lubricant such as magnesium stearate; and asweetening agent such as sucrose, lactose, or saccharin. When the dosageunit form is a capsule, it can contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets can be coatedwith shellac, sugar, or both. A syrup can contain, in addition to activeingredient, sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye, and flavoring such as cherry or orange flavor.

For oral therapeutic administration, these active compounds can beincorporated with excipients and used in the form of tablets, capsules,elixirs, suspensions, syrups, and the like. Such compositions andpreparations should contain at least 0.1% of active compound. Thepercentage of the compound in these compositions can, of course, bevaried and can conveniently be between about 2% to about 60% of theweight of the unit. The amount of active compound in suchtherapeutically useful compositions is such that a suitable dosage willbe obtained. Preferred compositions according to the present inventionare prepared so that an oral dosage unit contains between about 1 mg and800 mg of active compound.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent, or with an assailableedible carrier, or they can be enclosed in hard or soft shell capsules,or they can be compressed into tablets, or they can be incorporateddirectly with the food of the diet.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form should be sterile and should befluid to the extent that easy syringability exists. It should be stableunder the conditions of manufacture and storage and should be preservedagainst the contaminating action of microorganisms, such as bacteria andfungi. The carrier can be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (e.g., glycerol, propylene glycol, andliquid polyethylene glycol), suitable mixtures thereof, and vegetableoils.

The compounds or pharmaceutical compositions of the present inventionmay also be administered in injectable dosages by solution or suspensionof these materials in a physiologically acceptable diluent with apharmaceutical adjuvant, carrier or excipient. Such adjuvants, carriersand/or excipients include, but are not limited to, sterile liquids, suchas water and oils, with or without the addition of a surfactant andother pharmaceutically and physiologically acceptable components.Illustrative oils are those of petroleum, animal, vegetable, orsynthetic origin, for example, peanut oil, soybean oil, or mineral oil.In general, water, saline, aqueous dextrose and related sugar solution,and glycols, such as propylene glycol or polyethylene glycol, arepreferred liquid carriers, particularly for injectable solutions.

These active compounds may also be administered parenterally. Solutionsor suspensions of these active compounds can be prepared in watersuitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols, and mixtures thereof in oils. Illustrative oils are those ofpetroleum, animal, vegetable, or synthetic origin, for example, peanutoil, soybean oil, or mineral oil. In general, water, saline, aqueousdextrose and related sugar solution, and glycols such as, propyleneglycol or polyethylene glycol, are preferred liquid carriers,particularly for injectable solutions. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

For use as aerosols, the compounds of the present invention in solutionor suspension may be packaged in a pressurized aerosol containertogether with suitable propellants, for example, hydrocarbon propellantslike propane, butane, or isobutane with conventional adjuvants. Thematerials of the present invention also may be administered in anon-pressurized form such as in a nebulizer or atomizer.

In one embodiment, the compounds of this invention are administered incombination with an anti-cancer agent. In one embodiment, theanti-cancer agent is a monoclonal antibody. In some embodiments, themonoclonal antibodies are used for diagnosis, monitoring, or treatmentof cancer. In one embodiment, monoclonal antibodies react againstspecific antigens on cancer cells. In one embodiment, the monoclonalantibody acts as a cancer cell receptor antagonist. In one embodiment,monoclonal antibodies enhance the patient's immune response. In oneembodiment, monoclonal antibodies act against cell growth factors, thusblocking cancer cell growth. In one embodiment, anti-cancer monoclonalantibodies are conjugated or linked to anti-cancer drugs, radioisotopes,other biologic response modifiers, other toxins, or a combinationthereof. In one embodiment, anti-cancer monoclonal antibodies areconjugated or linked to a compound of this invention as describedhereinabove.

Yet another aspect of the present invention relates to a method oftreating cancer that includes selecting a subject in need of treatmentfor cancer, and administering to the subject a pharmaceuticalcomposition comprising a compound according to the first aspect of thepresent invention and a pharmaceutically acceptable carrier underconditions effective to treat cancer.

When administering the compounds of the present invention, they can beadministered systemically or, alternatively, they can be administereddirectly to a specific site where cancer cells or precancerous cells arepresent. Thus, administering can be accomplished in any manner effectivefor delivering the compounds or the pharmaceutical compositions to thecancer cells or precancerous cells. Exemplary modes of administrationinclude, without limitation, administering the compounds or compositionsorally, topically, transdermally, parenterally, subcutaneously,intravenously, intramuscularly, intraperitoneally, by intranasalinstillation, by intracavitary or intravesical instillation,intraocularly, intraarterially, intralesionally, or by application tomucous membranes, such as, that of the nose, throat, and bronchialtubes.

Biological Activity

In one embodiment, the invention provides compounds and compositions,including any embodiment described herein, for use in any of the methodsof this invention. In one embodiment, use of a compound of thisinvention or a composition comprising the same, will have utility ininhibiting, suppressing, enhancing or stimulating a desired response ina subject, as will be understood by one skilled in the art. In anotherembodiment, the compositions may further comprise additional activeingredients, whose activity is useful for the particular application forwhich the compound of this invention is being administered.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the severity, reducing the risk of developing orinhibiting cancer comprising administering a compound of this inventionto a subject suffering from cancer under conditions effective to treatthe cancer.

Drug resistance is the major cause of cancer chemotherapy failure. Onemajor contributor to multidrug resistance is overexpression ofP-glycoprotein (P-gp). This protein is a clinically importanttransporter protein belonging to the ATP-binding cassette family of cellmembrane transporters. It can pump substrates including anticancer drugsout of tumor cells through an ATP-dependent mechanism.

In one embodiment, this invention provides methods for: a) treating,suppressing, reducing the severity, reducing the risk, or inhibitingdrug resistant tumors; b) treating, suppressing, reducing the severity,reducing the risk, or inhibiting metastatic cancer; c) treating,suppressing, reducing the severity, reducing the risk, or inhibitingdrug resistant cancer; d) treating, suppressing, reducing the severity,reducing the risk, or inhibiting a drug resistant cancer wherein thecancer is melanoma; e) a method of treating, suppressing, reducing theseverity, reducing the risk, or inhibiting a drug resistant cancerwherein the cancer is prostate cancer; f) a method of treating,suppressing, reducing the severity, reducing the risk, or inhibitingmetastatic melanoma; g) a method of treating, suppressing, reducing theseverity, reducing the risk, or inhibiting prostate cancer; h) treating,suppressing, reducing the severity, reducing the risk, or inhibitingcancer in a subject, wherein the subject has been previously treatedwith chemotherapy, radiotherapy, or biological therapy; comprising thestep of administering to said subject a compound of this inventionand/or an isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, tautomer, hydrate, N-oxide, polymorph, orcrystal of said compound, or any combination thereof.

The compounds of the present invention are useful in the treatment,reducing the severity, reducing the risk, or inhibition of cancer,metastatic cancer, drug resistant tumors, drug resistant cancer andvarious forms of cancer. In a preferred embodiment the cancer isprostate cancer, breast cancer, ovarian cancer, skin cancer (e.g.,melanoma), lung cancer, colon cancer, leukemia, lymphoma, head and neck,pancreatic, esophageal, renal cancer or CNS cancer (e.g., glioma,glioblastoma). Treatment of these different cancers is supported by theExamples herein. Moreover, based upon their believed mode of action astubulin inhibitors, it is believed that other forms of cancer willlikewise be treatable or preventable upon administration of thecompounds or compositions of the present invention to a patient.Preferred compounds of the present invention are selectively disruptiveto cancer cells, causing ablation of cancer cells but preferably notnormal cells. Significantly, harm to normal cells is minimized becausethe cancer cells are susceptible to disruption at much lowerconcentrations of the compounds of the present invention.

In some embodiments, this invention provides for the use of a compoundas herein described, or its isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, tautomer, polymorph, crystal,N-oxide, hydrate or any combination thereof, for treating, suppressing,reducing the severity, reducing the risk, or inhibiting cancer in asubject. In another embodiment, the cancer is adrenocortical carcinoma,anal cancer, bladder cancer, brain tumor, brain stem, breast cancer,glioma, cerebellar astrocytoma, cerebral astrocytoma, ependymoma,medulloblastoma, supratentorial primitive neuroectodermal, pinealtumors, hypothalamic glioma, breast cancer, carcinoid tumor, carcinoma,cervical cancer, colon cancer, central nervous system (CNS) cancer,endometrial cancer, esophageal cancer, extrahepatic bile duct cancer,Ewing's family of tumors (Pnet), extracranial germ cell tumor, eyecancer, intraocular melanoma, gallbladder cancer, gastric cancer, germcell tumor, extragonadal, gestational trophoblastic tumor, head and neckcancer, hypopharyngeal cancer, islet cell carcinoma, laryngeal cancer,leukemia, acute lymphoblastic, leukemia, oral cavity cancer, livercancer, lung cancer, non-small cell lung cancer, small cell, lymphoma,AIDS-related lymphoma, central nervous system (primary), lymphoma,cutaneous T-cell, lymphoma, Hodgkin's disease, non-Hodgkin's disease,malignant mesothelioma, melanoma, Merkel cell carcinoma, metasticsquamous carcinoma, multiple myeloma, plasma cell neoplasms, mycosisfungoides, myelodysplastic syndrome, myeloproliferative disorders,nasopharyngeal cancer, neuroblastoma, oropharyngeal cancer,osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germcell tumor, ovarian low malignant potential tumor, pancreatic cancer,exocrine, pancreatic cancer, islet cell carcinoma, paranasal sinus andnasal cavity cancer, parathyroid cancer, penile cancer, pheochromocytomacancer, pituitary cancer, plasma cell neoplasm, prostate cancer,rhabdomyosarcoma, rectal cancer, renal cancer, renal cell cancer,salivary gland cancer, Sezary syndrome, skin cancer, cutaneous T-celllymphoma, skin cancer, Kaposi's sarcoma, skin cancer, melanoma, smallintestine cancer, soft tissue sarcoma, soft tissue sarcoma, testicularcancer, thymoma, malignant, thyroid cancer, urethral cancer, uterinecancer, sarcoma, unusual cancer of childhood, vaginal cancer, vulvarcancer, Wilms' tumor, or any combination thereof. In another embodimentthe subject has been previously treated with chemotherapy, radiotherapyor biological therapy.

In some embodiments, this invention provides for the use of a compoundas herein described, or its isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, tautomer, polymorph, crystal,N-oxide, hydrate or any combination thereof, for treating, suppressing,reducing the severity, reducing the risk, or inhibiting a metastaticcancer in a subject. In another embodiment, the cancer is adrenocorticalcarcinoma, anal cancer, bladder cancer, brain tumor, brain stem, breastcancer, glioma, cerebellar astrocytoma, cerebral astrocytoma,ependymoma, medulloblastoma, supratentorial primitive neuroectodermal,pineal tumors, hypothalamic glioma, breast cancer, carcinoid tumor,carcinoma, cervical cancer, colon cancer, central nervous system (CNS)cancer, endometrial cancer, esophageal cancer, extrahepatic bile ductcancer, Ewing's family of tumors (Pnet), extracranial germ cell tumor,eye cancer, intraocular melanoma, gallbladder cancer, gastric cancer,germ cell tumor, extragonadal, gestational trophoblastic tumor, head andneck cancer, hypopharyngeal cancer, islet cell carcinoma, laryngealcancer, leukemia, acute lymphoblastic, leukemia, oral cavity cancer,liver cancer, lung cancer, non-small cell lung cancer, small cell,lymphoma, AIDS-related lymphoma, central nervous system (primary),lymphoma, cutaneous T-cell, lymphoma, Hodgkin's disease, non-Hodgkin'sdisease, malignant mesothelioma, melanoma, Merkel cell carcinoma,metasatic squamous carcinoma, multiple myeloma, plasma cell neoplasms,mycosis fungoides, myelodysplastic syndrome, myeloproliferativedisorders, nasopharyngeal cancer, neuroblastoma, oropharyngeal cancer,osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germcell tumor, ovarian low malignant potential tumor, pancreatic cancer,exocrine, pancreatic cancer, islet cell carcinoma, paranasal sinus andnasal cavity cancer, parathyroid cancer, penile cancer, pheochromocytomacancer, pituitary cancer, plasma cell neoplasm, prostate cancer,rhabdomyosarcoma, rectal cancer, renal cancer, renal cell cancer,salivary gland cancer, Sezary syndrome, skin cancer, cutaneous T-celllymphoma, skin cancer, Kaposi's sarcoma, skin cancer, melanoma, smallintestine cancer, soft tissue sarcoma, soft tissue sarcoma, testicularcancer, thymoma, malignant, thyroid cancer, urethral cancer, uterinecancer, sarcoma, unusual cancer of childhood, vaginal cancer, vulvarcancer, Wilms' tumor, or any combination thereof.

In some embodiments, this invention provides for the use of a compoundas herein described, or its isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, tautomer, polymorph, crystal,N-oxide, hydrate or any combination thereof, for treating, suppressing,reducing the severity, reducing the risk, or inhibiting a drug-resistantcancer or resistant cancer in a subject. In another embodiment, thecancer is adrenocortical carcinoma, anal cancer, bladder cancer, braintumor, brain stem, breast cancer, glioma, cerebellar astrocytoma,cerebral astrocytoma, ependymoma, medulloblastoma, supratentorialprimitive neuroectodermal, pineal tumors, hypothalamic glioma, breastcancer, carcinoid tumor, carcinoma, cervical cancer, colon cancer,central nervous system (CNS) cancer, endometrial cancer, esophagealcancer, extrahepatic bile duct cancer, Ewing's family of tumors (Pnet),extracranial germ cell tumor, eye cancer, intraocular melanoma,gallbladder cancer, gastric cancer, germ cell tumor, extragonadal,gestational trophoblastic tumor, head and neck cancer, hypopharyngealcancer, islet cell carcinoma, laryngeal cancer, leukemia, acutelymphoblastic, leukemia, oral cavity cancer, liver cancer, lung cancer,non-small cell lung cancer, small cell, lymphoma, AIDS-related lymphoma,central nervous system (primary), lymphoma, cutaneous T-cell, lymphoma,Hodgkin's disease, non-Hodgkin's disease, malignant mesothelioma,melanoma, Merkel cell carcinoma, metasatic squamous carcinoma, multiplemyeloma, plasma cell neoplasms, mycosis fungoides, myelodysplasticsyndrome, myeloproliferative disorders, nasopharyngeal cancer,neuroblastoma, oropharyngeal cancer, osteosarcoma, ovarian cancer,ovarian epithelial cancer, ovarian germ cell tumor, ovarian lowmalignant potential tumor, pancreatic cancer, exocrine, pancreaticcancer, islet cell carcinoma, paranasal sinus and nasal cavity cancer,parathyroid cancer, penile cancer, pheochromocytoma cancer, pituitarycancer, plasma cell neoplasm, prostate cancer, rhabdomyosarcoma, rectalcancer, renal cancer, renal cell cancer, salivary gland cancer, Sezarysyndrome, skin cancer, cutaneous T-cell lymphoma, skin cancer, Kaposi'ssarcoma, skin cancer, melanoma, small intestine cancer, soft tissuesarcoma, soft tissue sarcoma, testicular cancer, thymoma, malignant,thyroid cancer, urethral cancer, uterine cancer, sarcoma, unusual cancerof childhood, vaginal cancer, vulvar cancer, Wilms' tumor, or anycombination thereof.

In one embodiment “metastatic cancer” refers to a cancer that spread(metastasized) from its original site to another area of the body.Virtually all cancers have the potential to spread. Whether metastasesdevelop depends on the complex interaction of many tumor cell factors,including the type of cancer, the degree of maturity (differentiation)of the tumor cells, the location and how long the cancer has beenpresent, as well as other incompletely understood factors. Metastasesspread in three ways—by local extension from the tumor to thesurrounding tissues, through the bloodstream to distant sites or throughthe lymphatic system to neighboring or distant lymph nodes. Each kind ofcancer may have a typical route of spread. The tumor is called by theprimary site (ex. breast cancer that has spread to the brain is calledmetastatic breast cancer to the brain).

In one embodiment “drug-resistant cancer” refers to cancer cells thatacquire resistance to chemotherapy. Cancer cells can acquire resistanceto chemotherapy by a range of mechanisms, including the mutation oroverexpression of the drug target, inactivation of the drug, orelimination of the drug from the cell. Tumors that recur after aninitial response to chemotherapy may be resistant to multiple drugs(they are multidrug resistant). In the conventional view of drugresistance, one or several cells in the tumor population acquire geneticchanges that confer drug resistance. Accordingly, the reasons for drugresistance, inter alia, are: a) some of the cells that are not killed bythe chemotherapy mutate (change) and become resistant to the drug. Oncethey multiply, there may be more resistant cells than cells that aresensitive to the chemotherapy; b) Gene amplification. A cancer cell mayproduce hundreds of copies of a particular gene. This gene triggers anoverproduction of protein that renders the anticancer drug ineffective;c) cancer cells may pump the drug out of the cell as fast as it is goingin using a molecule called p-glycoprotein; d) cancer cells may stoptaking in the drugs because the protein that transports the drug acrossthe cell wall stops working; e) the cancer cells may learn how to repairthe DNA breaks caused by some anti-cancer drugs; f) cancer cells maydevelop a mechanism that inactivates the drug. One major contributor tomultidrug resistance is overexpression of P-glycoprotein (P-gp). Thisprotein is a clinically important transporter protein belonging to theATP-binding cassette family of cell membrane transporters. It can pumpsubstrates including anticancer drugs out of tumor cells through anATP-dependent mechanism. Thus, the resistance to anticancer agents usedin chemotherapy is the main cause of treatment failure in malignantdisorders, provoking tumors to become resistant. Drug resistance is themajor cause of cancer chemotherapy failure.

In one embodiment “resistant cancer” refers to drug-resistant cancer asdescribed herein above. In another embodiment “resistant cancer” refersto cancer cells that acquire resistance to any treatment such aschemotherapy, radiotherapy or biological therapy.

In one embodiment, this invention is directed to treating, suppressing,reducing the severity, reducing the risk, or inhibiting cancer in asubject, wherein the subject has been previously treated withchemotherapy, radiotherapy or biological therapy.

In one embodiment “Chemotherapy” refers to chemical treatment for cancersuch as drugs that kill cancer cells directly. Such drugs are referredas “anti-cancer” drugs or “antineoplastics.” Today's therapy uses morethan 100 drugs to treat cancer. To cure a specific cancer. Chemotherapyis used to control tumor growth when cure is not possible; to shrinktumors before surgery or radiation therapy; to relieve symptoms (such aspain); and to destroy microscopic cancer cells that may be present afterthe known tumor is removed by surgery (called adjuvant therapy).Adjuvant therapy is given to prevent a possible cancer reoccurrence.

In one embodiment, “Radiotherapy” refers to high energy x-rays andsimilar rays (such as electrons) to treat disease. Many people withcancer will have radiotherapy as part of their treatment. This can begiven either as external radiotherapy from outside the body using x-raysor from within the body as internal radiotherapy. Radiotherapy works bydestroying the cancer cells in the treated area. Although normal cellscan also be damaged by the radiotherapy, they can usually repairthemselves. Radiotherapy treatment can cure some cancers and can alsoreduce the chance of a cancer coming back after surgery. It may be usedto reduce cancer symptoms.

In one embodiment “Biological therapy” refers to substances that occurnaturally in the body to destroy cancer cells. There are several typesof treatment including: monoclonal antibodies, cancer growth inhibitors,vaccines and gene therapy. Biological therapy is also known asimmunotherapy.

In one embodiment, this invention provides a method of treating asubject suffering from prostate cancer, metastatic prostate cancer,resistant prostate cancer or drug-resistant prostate cancer comprisingthe step of administering to said subject a compound of this invention,or its isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, tautomer, hydrate, N-oxide, polymorph, crystalor any combination thereof, or a composition comprising the same in anamount effective to treat prostate cancer in the subject. In anotherembodiment, the compound is compound 12 db. In another embodiment, thecompound is compound 11cb. In another embodiment, the compound iscompound 11fb. In another embodiment, the compound is compound 12da. Inanother embodiment, the compound is compound 12fa. In anotherembodiment, the compound is compound 12fb. In another embodiment, thecompound is compound 12cb. In another embodiment, the compound iscompound 55. In another embodiment, the compound is compound 6b. Inanother embodiment, the compound is compound 17ya.

In one embodiment, this invention provides a method for suppressing,reducing the severity, reducing the risk, delaying the progression, orinhibiting prostate cancer, metastatic prostate cancer, resistantprostate cancer or drug-resistant prostate cancer in a subject,comprising administering to the subject a compound of this inventionand/or its isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, tautomer, hydrate, N-oxide, polymorph, crystalor any combination thereof or a composition comprising the same. Inanother embodiment, the compound is compound 12 db. In anotherembodiment, the compound is compound 11cb. In another embodiment, thecompound is compound 11fb. In another embodiment, the compound iscompound 12da. In another embodiment, the compound is compound 12fa. Inanother embodiment, the compound is compound 12fb. In anotherembodiment, the compound is compound 12cb. In another embodiment, thecompound is compound 55. In another embodiment, the compound is compound6b. In another embodiment, the compound is compound 17ya.

In one embodiment, this invention provides a method of treating asubject suffering from breast cancer, metastatic breast cancer,resistant breast cancer or drug-resistant breast cancer comprising thestep of administering to said subject a compound of this invention, orits isomer, metabolite, pharmaceutically acceptable salt, pharmaceuticalproduct, tautomer, hydrate, N-oxide, polymorph, crystal or anycombination thereof, or a composition comprising the same. In anotherembodiment, the subject is a male or female. In another embodiment, thecompound is compound 12 db. In another embodiment, the compound iscompound 11cb. In another embodiment, the compound is compound 11fb. Inanother embodiment, the compound is compound 12da. In anotherembodiment, the compound is compound 12fa. In another embodiment, thecompound is compound 12fb. In another embodiment, the compound iscompound 12cb. In another embodiment, the compound is compound 55. Inanother embodiment, the compound is compound 6b. In another embodiment,the compound is compound 17ya.

In one embodiment, this invention provides a method of suppressing,reducing the severity, reducing the risk, delaying the progression, orinhibiting breast cancer, metastatic breast cancer, resistant breastcancer or drug-resistant breast cancer in a subject comprising the stepof administering to said subject a compound of this invention or itsisomer, metabolite, pharmaceutically acceptable salt, pharmaceuticalproduct, tautomer, hydrate, N-oxide, polymorph, crystal or anycombination thereof, or a composition comprising the same. In anotherembodiment, the subject is a male or female. In another embodiment, thecompound is compound 12 db. In another embodiment, the compound iscompound 11cb. In another embodiment, the compound is compound 11fb. Inanother embodiment, the compound is compound 12da. In anotherembodiment, the compound is compound 12fa. In another embodiment, thecompound is compound 12M. In another embodiment, the compound iscompound 12cb. In another embodiment, the compound is compound 55. Inanother embodiment, the compound is compound 6b. In another embodiment,the compound is compound 17ya.

In another embodiment, this invention provides for the use of a compoundas herein described, or its isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide,polymorph, crystal or any combination thereof, for treating,suppressing, reducing the severity, reducing the risk, delaying theprogression, or inhibiting ovarian cancer, metastatic ovarian cancer,resistant ovarian cancer or drug-resistant ovarian cancer in a subject.In another embodiment, the compound is compound 12 db. In anotherembodiment, the compound is compound 11cb. In another embodiment, thecompound is compound 11fb. In another embodiment, the compound iscompound 12da. In another embodiment, the compound is compound 12fa. Inanother embodiment, the compound is compound 12fb. In anotherembodiment, the compound is compound 12cb. In another embodiment, thecompound is compound 55. In another embodiment, the compound is compound6b. In another embodiment, the compound is compound 17ya.

In one embodiment, this invention provides a method for treating,suppressing, reducing the severity, reducing the risk or inhibitingmelanoma, metastatic melanoma, resistant melanoma or drug-resistantmelanoma in a subject, comprising administering to the subject acompound of this invention and/or its isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, tautomer,hydrate, N-oxide, polymorph, crystal or any combination thereof. Inanother embodiment, the compound is compound 12 db. In anotherembodiment, the compound is compound 11cb. In another embodiment, thecompound is compound 11fb. In another embodiment, the compound iscompound 12da. In another embodiment, the compound is compound 12fa. Inanother embodiment, the compound is compound 12fb. In anotherembodiment, the compound is compound 12cb. In another embodiment, thecompound is compound 55. In another embodiment, the compound is compound6b. In another embodiment, the compound is compound 17ya.

In another embodiment, this invention provides for the use of a compoundas herein described, or isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph,crystal or any combination thereof, for treating, suppressing, reducingthe severity, reducing the risk, delaying the progression, or inhibitinglung cancer, metastatic lung cancer, resistant lung cancer ordrug-resistant lung cancer. In another embodiment, the compound iscompound 12 db. In another embodiment, the compound is compound 11cb. Inanother embodiment, the compound is compound 11fb. In anotherembodiment, the compound is compound 12da. In another embodiment, thecompound is compound 12fa. In another embodiment, the compound iscompound 12fb. In another embodiment, the compound is compound 12cb. Inanother embodiment, the compound is compound 55. In another embodiment,the compound is compound 6b. In another embodiment, the compound iscompound 17ya.

In another embodiment, this invention provides for the use of a compoundas herein described, or isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph,crystal any combination thereof, for treating, suppressing, reducing theseverity, reducing the risk, delaying the progression, or inhibitingnon-small cell lung cancer, metastatic small cell lung cancer, resistantsmall cell lung cancer or drug-resistant small cell lung cancer. Inanother embodiment, the compound is compound 12 db. In anotherembodiment, the compound is compound 11cb. In another embodiment, thecompound is compound 11fb. In another embodiment, the compound iscompound 12da. In another embodiment, the compound is compound 12fa. Inanother embodiment, the compound is compound 12fb. In anotherembodiment, the compound is compound 12cb. In another embodiment, thecompound is compound 55. In another embodiment, the compound is compound6b. In another embodiment, the compound is compound 17ya.

In another embodiment, this invention provides for the use of a compoundas herein described, or isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph,crystal any combination thereof, for treating, suppressing, reducing theseverity, reducing the risk, delaying the progression, or inhibitingcolon cancer, metastatic colon lung cancer, resistant colon cancer ordrug-resistant colon cancer. In another embodiment, the compound iscompound 12 db. In another embodiment, the compound is compound 11cb. Inanother embodiment, the compound is compound 11fb. In anotherembodiment, the compound is compound 12da. In another embodiment, thecompound is compound 12fa. In another embodiment, the compound iscompound 12fb. In another embodiment, the compound is compound 12cb. Inanother embodiment, the compound is compound 55. In another embodiment,the compound is compound 6b. In another embodiment, the compound iscompound 17ya.

In another embodiment, this invention provides for the use of a compoundas herein described, or isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph,crystal any combination thereof, for treating, suppressing, reducing theseverity, reducing the risk, delaying the progression, or inhibiting ofleukemia, metastatic leukemia, resistant leukemia or drug-resistantleukemia. In another embodiment, the compound is compound 12 db. Inanother embodiment, the compound is compound 11cb. In anotherembodiment, the compound is compound 11fb. In another embodiment, thecompound is compound 12da. In another embodiment, the compound iscompound 12fa. In another embodiment, the compound is compound 12fb. Inanother embodiment, the compound is compound 12cb. In anotherembodiment, the compound is compound 55. In another embodiment, thecompound is compound 6b. In another embodiment, the compound is compound17ya.

In another embodiment, this invention provides for the use of a compoundas herein described, or isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph,crystal any combination thereof, for treating, suppressing, reducing theseverity, reducing the risk, delaying the progression, or inhibitinglymphoma, metastatic lymphoma, lymphoma or drug-resistant lymphoma. Inanother embodiment, the compound is compound 12 db. In anotherembodiment, the compound is compound 11cb. In another embodiment, thecompound is compound 11fb. In another embodiment, the compound iscompound 12da. In another embodiment, the compound is compound 12fa. Inanother embodiment, the compound is compound 12fb. In anotherembodiment, the compound is compound 12cb. In another embodiment, thecompound is compound 55. In another embodiment, the compound is compound6b. In another embodiment, the compound is compound 17ya.

In another embodiment, this invention provides for the use of a compoundas herein described, or isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph,crystal any combination thereof, for treating, suppressing, reducing theseverity, reducing the risk, delaying the progression, or inhibitinghead and neck cancer, metastatic head and neck cancer, resistant headand neck cancer or drug-resistant head and neck cancer. In anotherembodiment, the compound is compound 12 db. In another embodiment, thecompound is compound 11cb. In another embodiment, the compound iscompound 11fb. In another embodiment, the compound is compound 12da. Inanother embodiment, the compound is compound 12fa. In anotherembodiment, the compound is compound 12fb. In another embodiment, thecompound is compound 12cb. In another embodiment, the compound iscompound 55. In another embodiment, the compound is compound 6b. Inanother embodiment, the compound is compound 17ya.

In another embodiment, this invention provides for the use of a compoundas herein described, or isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph,crystal any combination thereof, for treating, suppressing, reducing theseverity, reducing the risk, delaying the progression, or inhibiting ofpancreatic cancer, metastatic pancreatic cancer, resistant pancreaticcancer or drug-resistant pancreatic cancer. In another embodiment, thecompound is compound 12 db. In another embodiment, the compound iscompound 11cb. In another embodiment, the compound is compound 11fb. Inanother embodiment, the compound is compound 12da. In anotherembodiment, the compound is compound 12fa. In another embodiment, thecompound is compound 12fb. In another embodiment, the compound iscompound 12cb. In another embodiment, the compound is compound 55. Inanother embodiment, the compound is compound 6b. In another embodiment,the compound is compound 17ya.

In another embodiment, this invention provides for the use of a compoundas herein described, or isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph,crystal any combination thereof, for treating, suppressing, reducing theseverity, reducing the risk, delaying the progression, or inhibitingesophageal cancer, metastatic esophageal cancer, resistant esophagealcancer or drug-resistant esophageal cancer. In another embodiment, thecompound is compound 12 db. In another embodiment, the compound iscompound 11cb. In another embodiment, the compound is compound 11fb. Inanother embodiment, the compound is compound 12da. In anotherembodiment, the compound is compound 12fa. In another embodiment, thecompound is compound 12fb. In another embodiment, the compound iscompound 12cb. In another embodiment, the compound is compound 55. Inanother embodiment, the compound is compound 6b. In another embodiment,the compound is compound 17ya.

In another embodiment, this invention provides for the use of a compoundas herein described, or isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph,crystal any combination thereof, for treating, suppressing, reducing theseverity, reducing the risk, delaying the progression, or inhibitingrenal cancer, metastatic renal cancer, resistant renal cancer ordrug-resistant renal cancer. In another embodiment, the compound iscompound 12 db. In another embodiment, the compound is compound 11cb. Inanother embodiment, the compound is compound 11fb. In anotherembodiment, the compound is compound 12da. In another embodiment, thecompound is compound 12fa. In another embodiment, the compound iscompound 12fb. In another embodiment, the compound is compound 12cb. Inanother embodiment, the compound is compound 55. In another embodiment,the compound is compound 6b. In another embodiment, the compound iscompound 17ya.

In another embodiment, this invention provides for the use of a compoundas herein described, or isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph,crystal any combination thereof, for treating, suppressing, reducing theseverity, reducing the risk, delaying the progression, or inhibiting CNScancer, metastatic CNS cancer, resistant CNS cancer or drug-resistantCNS cancer. In another embodiment, the compound is compound 12 db. Inanother embodiment, the compound is compound 11cb. In anotherembodiment, the compound is compound 11fb. In another embodiment, thecompound is compound 12da. In another embodiment, the compound iscompound 12fa. In another embodiment, the compound is compound 12fb. Inanother embodiment, the compound is compound 12cb. In anotherembodiment, the compound is compound 55. In another embodiment, thecompound is compound 6b. In another embodiment, the compound is compound17ya.

In some embodiments, this invention provides for the use of a compoundas herein described, or its isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, tautomer, polymorph, crystal,N-oxide, hydrate or any combination thereof, for treating, suppressing,reducing the severity, reducing the risk, or inhibiting a drug resistantcancerous tumor or tumors in a subject. In another embodiment, thecancer is adrenocortical carcinoma, anal cancer, bladder cancer, braintumor, brain stem, breast cancer, glioma, cerebellar astrocytoma,cerebral astrocytoma, ependymoma, medulloblastoma, supratentorialprimitive neuroectodermal, pineal tumors, hypothalamic glioma, breastcancer, carcinoid tumor, carcinoma, cervical cancer, colon cancer,central nervous system (CNS) cancer, endometrial cancer, esophagealcancer, extrahepatic bile duct cancer, Ewing's family of tumors (Pnet),extracranial germ cell tumor, eye cancer, intraocular melanoma,gallbladder cancer, gastric cancer, germ cell tumor, extragonadal,gestational trophoblastic tumor, head and neck cancer, hypopharyngealcancer, islet cell carcinoma, laryngeal cancer, leukemia, acutelymphoblastic, leukemia, oral cavity cancer, liver cancer, lung cancer,non-small cell lung cancer, small cell, lymphoma, AIDS-related lymphoma,central nervous system (primary), lymphoma, cutaneous T-cell, lymphoma,Hodgkin's disease, non-Hodgkin's disease, malignant mesothelioma,melanoma, Merkel cell carcinoma, metasatic squamous carcinoma, multiplemyeloma, plasma cell neoplasms, mycosis fungoides, myelodysplasticsyndrome, myeloproliferative disorders, nasopharyngeal cancer,neuroblastoma, oropharyngeal cancer, osteosarcoma, ovarian cancer,ovarian epithelial cancer, ovarian germ cell tumor, ovarian lowmalignant potential tumor, pancreatic cancer, exocrine, pancreaticcancer, islet cell carcinoma, paranasal sinus and nasal cavity cancer,parathyroid cancer, penile cancer, pheochromocytoma cancer, pituitarycancer, plasma cell neoplasm, prostate cancer, rhabdomyosarcoma, rectalcancer, renal cancer, renal cell cancer, salivary gland cancer, Sezarysyndrome, skin cancer, cutaneous T-cell lymphoma, skin cancer, Kaposi'ssarcoma, skin cancer, melanoma, small intestine cancer, soft tissuesarcoma, soft tissue sarcoma, testicular cancer, thymoma, malignant,thyroid cancer, urethral cancer, uterine cancer, sarcoma, unusual cancerof childhood, vaginal cancer, vulvar cancer, Wilms' tumor, or anycombination thereof. In another embodiment, the compound is compound 12db. In another embodiment, the compound is compound 11cb. In anotherembodiment, the compound is compound 11fb. In another embodiment, thecompound is compound 12da. In another embodiment, the compound iscompound 12fa. In another embodiment, the compound is compound 12fb. Inanother embodiment, the compound is compound 12cb. In anotherembodiment, the compound is compound 55. In another embodiment, thecompound is compound 6b. In another embodiment, the compound is compound17ya.

In another embodiment, the tumor is prostate cancer tumor. In anotherembodiment, the tumor is ovarian cancer tumor. In another embodiment,the tumor is a melanoma tumor. In another embodiment, the tumor is amultidrug resistant (MDR) melanoma tumor.

In one embodiment, this invention is directed to a method of destroyinga cancerous cell comprising: providing a compound of this invention andcontacting the cancerous cell with the compound under conditionseffective to destroy the contacted cancerous cell. According to variousembodiments of destroying the cancerous cells, the cells to be destroyedcan be located either in vivo or ex vivo (i.e., in culture). In anotherembodiment, the compound is compound 12 db. In another embodiment, thecompound is compound 11cb. In another embodiment, the compound iscompound 11fb. In another embodiment, the compound is compound 12da. Inanother embodiment, the compound is compound 12fa. In anotherembodiment, the compound is compound 12fb. In another embodiment, thecompound is compound 12cb. In another embodiment, the compound iscompound 55. In another embodiment, the compound is compound 6b. Inanother embodiment, the compound is compound 17ya.

In another embodiment, the cancer is selected from the group consistingof prostate cancer, breast cancer, ovarian cancer, skin cancer,melanoma, lung cancer, colon cancer, leukemia, renal cancer, CNS cancer,and combinations thereof.

A still further aspect of the present invention relates to a method oftreating or preventing a cancerous condition that includes: providing acompound of the present invention and then administering an effectiveamount of the compound to a patient in a manner effective to treat orprevent a cancerous condition.

According to one embodiment, the patient to be treated is characterizedby the presence of a precancerous condition, and the administering ofthe compound is effective to prevent development of the precancerouscondition into the cancerous condition. This can occur by destroying theprecancerous cell prior to or concurrent with its further developmentinto a cancerous state.

According to another embodiment, the patient to be treated ischaracterized by the presence of a cancerous condition, and theadministering of the compound is effective either to cause regression ofthe cancerous condition or to inhibit growth of the cancerous condition,i.e., stopping its growth altogether or reducing its rate of growth.This preferably occurs by destroying cancer cells, regardless of theirlocation in the patient body. That is, whether the cancer cells arelocated at a primary tumor site or whether the cancer cells havemetastasized and created secondary tumors within the patient body.

As used herein, subject or patient refers to any mammalian patient,including without limitation, humans and other primates, dogs, cats,horses, cows, sheep, pigs, rats, mice, and other rodents. In oneembodiment, the subject is male. In another embodiment, the subject isfemale. In some embodiments, while the methods as described herein maybe useful for treating either males or females.

When administering the compounds of the present invention, they can beadministered systemically or, alternatively, they can be administereddirectly to a specific site where cancer cells or precancerous cells arepresent. Thus, administering can be accomplished in any manner effectivefor delivering the compounds or the pharmaceutical compositions to thecancer cells or precancerous cells. Exemplary modes of administrationinclude, without limitation, administering the compounds or compositionsorally, topically, transdermally, parenterally, subcutaneously,intravenously, intramuscularly, intraperitoneally, by intranasalinstillation, by intracavitary or intravesical instillation,intraocularly, intraarterially, intralesionally, or by application tomucous membranes, such as, that of the nose, throat, and bronchialtubes.

The compounds of the present invention are useful in the treatment orprevention of various forms of cancer, particularly prostate cancer,breast cancer, ovarian, skin cancer (e.g., melanoma), lung cancer, coloncancer, leukemia, renal cancer, and CNS cancer (e.g., glioma,glioblastoma). Treatment of these different cancers is supported by theExamples herein. Moreover, based upon their believed mode of action astubulin inhibitors, it is believed that other forms of cancer willlikewise be treatable or preventable upon administration of thecompounds or compositions of the present invention to a patient.Preferred compounds of the present invention are selectively disruptiveto cancer cells, causing ablation of cancer cells but preferably notnormal cells. Significantly, harm to normal cells is minimized becausethe cancer cells are susceptible to disruption at much lowerconcentrations of the compounds of the present invention.

The compounds of the present invention are useful in the treatment,reducing the severity, reducing the risk, or inhibition of cancer,metastatic cancer, resistant cancer or drug-resistant cancer. In anotherembodiment, the cancer is prostate cancer, breast cancer, ovarian, skincancer (e.g., melanoma), lung cancer, colon cancer, leukemia, lymphoma,head and neck, pancreatic, esophageal, renal cancer or CNS cancer.Treatment of these different cancers is supported by the Examplesherein. Moreover, based upon their believed mode of action as tubulininhibitors, it is believed that other forms of cancer will likewise betreatable or preventable upon administration of the compounds orcompositions of the present invention to a patient. Preferred compoundsof the present invention are selectively disruptive to cancer cells,causing ablation of cancer cells but preferably not normal cells.Significantly, harm to normal cells is minimized because the cancercells are susceptible to disruption at much lower concentrations of thecompounds of the present invention. In another embodiment, the compoundis compound 12 db. In another embodiment, the compound is compound 11cb.In another embodiment, the compound is compound 11fb. In anotherembodiment, the compound is compound 12da. In another embodiment, thecompound is compound 12fa. In another embodiment, the compound iscompound 12fb. In another embodiment, the compound is compound 12cb. Inanother embodiment, the compound is compound 55. In another embodiment,the compound is compound 6b. In another embodiment, the compound iscompound 17ya.

As used herein, subject or patient refers to any mammalian patient,including without limitation, humans and other primates, dogs, cats,horses, cows, sheep, pigs, rats, mice, and other rodents. In someembodiments, while the methods as described herein may be useful fortreating either males or females.

In one embodiment, the compound is administered in combination with ananti-cancer agent by administering the compounds as herein described,alone or in combination with other agents.

When the compounds or pharmaceutical compositions of the presentinvention are administered to treat, suppress, reduce the severity,reduce the risk, or inhibit a cancerous condition, the pharmaceuticalcomposition can also contain, or can be administered in conjunctionwith, other therapeutic agents or treatment regimen presently known orhereafter developed for the treatment of various types of cancer.Examples of other therapeutic agents or treatment regimen include,without limitation, radiation therapy, immunotherapy, chemotherapy,surgical intervention, and combinations thereof.

The following examples are presented in order to more fully illustratethe preferred embodiments of the invention. They should in no way,however, be construed as limiting the broad scope of the invention.

EXAMPLES

The Examples set forth below are for illustrative purposes only and arenot intended to limit, in any way, the scope of the present invention.

Materials and Methods:

General. All reagents were purchased from Sigma-Aldrich Chemical Co.,Fisher Scientific (Pittsburgh, Pa.), AK Scientific (Mountain View,Calif.), Oakwood Products (West Columbia, S.C.), etc. and were usedwithout further purification. Moisture-sensitive reactions were carriedunder an argon atmosphere. ABT-751 was prepared according methodsreported by Yoshino et al.²⁶ Routine thin layer chromatography (TLC) wasperformed on aluminum backed Uniplates (Analtech, Newark, Del.). Meltingpoints were measured with Fisher-Johns melting point apparatus(uncorrected). ¹H NMR spectra were obtained on a Bruker AX 300(Billerica, Mass.) spectrometer or Varian Inova-500 (Vernon Hills, Ill.)spectrometer. Chemical shifts are reported as parts per million (ppm)relative to TMS in CDCl₃. Mass spectral data was collected on a BrukerESQUIRE electrospray/ion trap instrument in positive and negative ionmodes. Elemental analyses were performed by Atlantic Microlab Inc.

Cell Culture and Cytotoxicity Assay of Prostate Cancer and Melanoma. Allcell lines were obtained from ATCC (American Type Culture Collection,Manassas, Va., USA), while cell culture supplies were purchased fromCellgro Mediatech (Herndon, Va., USA). We examined the antiproliferativeactivity of our anti-tubulin compounds in four human prostate cancercell lines (LNCaP, DU 145, PC-3, and PPC-1) and two human melanoma celllines (A375 and WM-164). Human ovarian cell line OVCAR-8 and itsresistant cell line that over-expresses P-gp (NCl/ADR-RES) were used asMDR models. Both ovarian cell lines were obtained from National CancerInstitutes (NCl). All cell lines were tested and authenticated by eitherATCC or NCI. All prostate cancer and ovarian cancer cell lines werecultured in RPMI 1640, supplemented with 10% fetal bovine serum (FBS).Melanoma cells were cultured in DMEM, supplemented with 5% FBS, 1%antibiotic/antimycotic mixture (Sigma-Aldrich, Inc., St. Louis, Mo.,USA) and bovine insulin (5 μ/mL; Sigma-Aldrich). The cytotoxic potentialof the anti-tubulin compounds was evaluated using the sulforhodamine B(SRB) assay after 96 h of treatment.

Aqueous Solubility. The solubility of drugs was determined byMultiscreen Solubility Filter Plate (Millipore Corporate, Billerica,Mass.) coupled with LC-MS/MS. Briefly, 198 μL of phosphate bufferedsaline (PBS) buffer (pH 7.4) was loaded into 96-well plate, and 2 μL of10 mM test compounds (in DMSO) was dispensed and mixed with gentleshaking (200-300 rpm) for 1.5 h at RT (N=3). The plate was centrifugedat 800 g for 5 min, and the filtrate was used to determine itsconcentration and solubility of test compound by LC-MS/MS as describedbelow.

Pharmacokinetic Study. Female Sprague-Dawley rats (n=3 or 4; 254±4 g)were purchased from Harlan Inc. (Indianapolis, Ind.). Rat thoracicjugular vein catheters were purchased from Braintree Scientific Inc.(Braintree, Mass.). On arrival at the animal facility, the animals wereacclimated for 3 days in a temperature-controlled room (20-22° C.) witha 12-h light/dark cycle before any treatment. Compound 1h wasadministered intravenously (i.v.) into the jugular vein catheters at adose of 2.5 mg/kg (in DMSO/PEG300, 2/8), whereas 5Ha and 5Hc were dosedat 5 mg/kg (in DMSO/PEG300, 1/9). An equal volume of heparinized salinewas injected to replace the removed blood, and blood samples (250 μL)were collected via the jugular vein catheters at 10, 20, 30 min, and 1,2, 4, 8, 12, 24 hr. Compounds 1h, 5Ha and 5Hc were given (p.o.) by oralgavage at 10 mg/kg (in Tween80/DMSO/H₂O, 2/1/7). All blood samples (250μL) after oral administration were collected via the jugular veincatheters at 30, 60, 90 min, 120 min, 150 min, 180 min, 210 min, 240min, and 8, 12, 24 h. Heparinized syringes and vials were prepared priorto blood collection. Plasma samples were prepared by centrifuging theblood samples at 8,000 g for 5 min. All plasma samples were storedimmediately at −80° C. until analyzed.

Analytes were extracted from 100 μL of plasma with 200 μL ofacetonitrile containing 200 nM the internal standard((3,5-dimethoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone). The sampleswere thoroughly mixed, centrifuged, and the organic extract wastransferred to autosampler for LC-MS/MS analysis. Multiple reactionmonitoring (MRM) mode, scanning m/z 356→188 (compound 1h), m/z 371→203(compound 5Ha), m/z 389→221 (compound 5Hc), and m/z 309→171 (theinternal standard), was used to obtain the most sensitive signals. Thepharmacokinetic parameters were determined using non-compartmentalanalysis (WinNonlin, Pharsight Corporation, Mountain View, Calif.)

Analytical Method. Sample solution (10 μL) was injected into an Agilentseries HPLC system (Agilent 1100 Series Agilent 1100 Chemstation,Agilent Technology Co, Ltd). All analytes were separated on anarrow-bore C18 column (Alltech Alltima HP, 2.1×100 mm, 3 μm, Fisher,Fair Lawn, N.J.). Two gradient modes were used. Gradient mode was usedto achieve the separation of analytes using mixtures of mobile phase A[ACN/H₂O (5%/95%, v/v) containing 0.1% formic acid] and mobile phase B[ACN/H₂O (95%/5%, v/v) containing 0.1% formic acid] at a flow rate of300 μL/min. Mobile phase A was used at 15% from 0 to 1 min followed by alinearly programmed gradient to 100% of mobile phase B within 6 min,100% of mobile phase B was maintained for 0.5 min before a quick ramp to15% mobile phase A. Mobile phase A was continued for another 12 mintowards the end of analysis.

In Vitro Tubulin Polymerization Assay. Bovine brain tubulin (0.4mg, >97% pure) (Cytoskeleton, Denver, Colo.) was mixed with 10 μM of thetest compounds and incubated in 100 μl of general tubulin buffer (80 mMPIPES, 2.0 mM MgCl₂, 0.5 mM EGTA, and 1 mM GTP) at pH 6.9. Theabsorbance of wavelength at 340 nm was monitored every 1 min for 20 minby the SYNERGY 4 Microplate Reader (Bio-Tek Instruments, Winooski, Vt.).The spectrophotometer was set at 37° C. for tubulin polymerization.

A triple-quadruple mass spectrometer, API Qtrap 4000™ (AppliedBiosystems/MDS SCIEX, Concord, Ontario, Canada), operating with aTurboIonSpray source was used. The spraying needle voltage was set at 5kV for positive mode. Curtain gas was set at 10; Gas 1 and gas 2 wereset 50. Collision-Assisted-Dissociation (CAD) gas at medium and thesource heater probe temperature at 500° C. Data acquisition andquantitative processing were accomplished using Analyst™ software, Ver.1.4.1 (Applied Biosystems).

The purity of the final compounds was tested via RP-HPLC on a Waters2695 HPLC system installed with a Photodiode Array Detector. Two RP-HPLCmethods were conducted using a Supelco Ascentis™ 5 μM C-18 column(250×4.6 mm) at ambient temperature, and a flow rate of 0.7 mL/min.HPLC1: Gradient: Solvent A (water) and Solvent B (methanol): 0-20 min40-100% B (linear gradient), 20-27 min 100% B. HPLC2: Gradient: SolventA (water) and Solvent B (methanol): 0-15 min 40-100% B (lineargradient), 15-25 min 100% B. UV detection at 254 nm.

The compounds of this invention were prepared according to FIGS. 1-17.

Example 1 Synthesis of B Ring Variant Compounds

B ring variant compounds were synthesized according to FIGS. 1 and 2.

Oxazole B Ring: Synthesis of(2-Phenyl-oxazol-4-yl)-(3,4,5-trimethoxy-phenyl)-methanone (36a) (FIG.1)

(2R)-2-Phenyl-4,5-dihydro-oxazole-4-carboxylic acid methyl ester (32a).Acetyl chloride (6.8 mL) was added dropwise to ice-cold methanol (30mL). After the addition of L-serine (0.48 mmol), the reaction mixturewas warmed to room temperature (RT) and stirred overnight. Evaporationof the solvent gave white solid (2R)-3-hydroxy-2-methyl-propionic acidmethyl ester HCl salt, which was used without purification in the nextstep. Triethylamine (11 mL, 72.3 mmol) was added slowly to a solution ofethyl benzimidate hydrochloride (11.6 g, 62.8 mmol) in CH₂Cl₂ (150 mL).The reaction mixture was stirred at RT for 30 min and(2R)-3-hydroxy-2-methyl-propionic acid methyl ester HCl salt (13.5 g,79.6 mmol) was added by portion. The resulting mixture was stirred for48 h and concentrated under reduced pressure. The compound 32a wasseparated from flash column as a yellow oil (12.3 g, 95.9%). ¹H NMR(CDCl₃) δ 7.99-7.38 (m, 5H), 4.97 (dd, 1H, J=7.8 Hz, J=10.5 Hz), 4.70(t, 1H, J=8.7 Hz), 4.62 (dd, 1H, J=8.7 Hz, J=10.5 Hz), 3.82 (s, 3H); MS(ESI) m/z 206.1 (M+H)⁺.

(2R)-2-Phenyl-4,5-dihydro-oxazole-4-carboxylic acid (33a). To anice-cooled solution of 32a in MeOH/H₂O was added LiOH (2.5 equiv) withstirring. The mixture was allowed to warm to RT in 1h, concentrated invacuo, and the white solid was dissolved in H₂O and acidified with 1 NHCl to pH 2.0 and extracted with MgSO₄, filtered and concentrated invacuo to provide the acid 33a as a white solid (95.8%). ¹H NMR (CDCl₃) δ7.98 (d, 2H), 7.57-7.42 (m, 3H), 5.04 (dd, 1H, J=7.8 Hz, J=10.8 Hz),4.80 (t, 1H, J=8.7 Hz), 4.70 (dd, 1H, J=9.0 Hz, J=10.8 Hz); MS (ESI) m/z191.9 (M+H)⁺, 189.7 (M−H)⁻, 145.8 (M—COOH)⁻.

(2R)-2-Phenyl-4,5-dihydro-oxazole-4-carboxylic acid methoxy-methyl-amide(34a). To a mixture of 33a (5 mmol), EDCI (6 mmol), HOBt (5 mmol) andEt₃N (5 mmol) in CH₂Cl₂ (50 mL) was added HNCH₃OCH₃ (5 mmol) andstirring continued at RT for 6-8 h. The reaction mixture was dilutedwith CH₂Cl₂ (100 mL) and sequentially washed with water, satd. NaHCO₃,brine and dried over MgSO₄. The solvent was removed under reducedpressure to yield a crude product 34a, which was purified by columnchromatography as a white solid (61.0%). ¹H NMR (CDCl₃) δ 7.98-7.36 (m,5H), 7.57-7.42 (m, 3H), 5.35 (br, t, 1 H), 4.81 (br, t, 1H), 4.52 (dd,1H, J=8.7 Hz, J=10.2 Hz), 3.90 (s, 3H), 3.27 (s, 3H); MS (ESI) m/z 257.0(M+H)⁺.

(2R)-(2-Phenyl-4,5-dihydro-oxazol-4-yl)-(3,4,5-trimethoxy-phenyl)-methanone(35a). To a solution of n-BuLi (1.6 M, 0.713 mL) in 8 mL THF was added asolution of 3,4,5-trimethoxybromobenzene (1.09 mmol) in 3 mL THF under−78° C. The mixture was allowed to stir for 2 h and a solution ofWeinreb amide 34a (1.14 mmol) in 3 mL THF was charged. The temperaturewas allowed to increase at RT and stirred overnight. The reactionmixture was quenched with satd. NH₄Cl, extracted with ethyl ether, driedwith MgSO₄. The solvent was removed under reduced pressure to yield acrude product, which was purified by column chromatography to obtainpure compound 35a as a white solid (47.9%). NMR (CDCl₃) δ 7.97-7.94 (m,2H), 7.62 (s, 2H), 7.54-7.37 (m, 3H), 5.61 (q, 1H, J=7.5 Hz, 9.9 Hz),5.12 (t, 1H, J=7.5 Hz), 4.57 (q, 1H, J=7.8 Hz, 9.9 Hz), 3.96 (s, 6H),3.95 (s, 3H); MS (ESI) m/z 364.1 (M+Na)⁺, 340.1 (M—H)⁻.

(2-Phenyl-oxazol-4-yl)-(3,4,5-trimethoxy-phenyl)-methanone (36a). Amixture of 35a (1.48 mmol), CBrCl₃ (2.59 mmol) and DBU (2.97 mmol) inCH₂Cl₂ (20 mL) was stirred overnight. The reaction mixture was absorbedon silica gel and purified by column chromatography to yield pure 36a asdesired (61.6%). ¹H NMR (CDCl₃) δ 8.37 (s, 1H), 8.14-8.12 (m, 2H), 7.74(s, 2H), 7.52-7.49 (m, 3H), 3.97 (s, 9H); MS (ESI) m/z 362.1 (M+Na)⁺.

Benzene, pyrimidine, pyridine, furan, thiophene, thiazole, pyrazole andpiperidine B ring variants (FIG. 2): B ring variants (1a-1d, 1k) wereobtained from their corresponding acids (37a-37d, 37k). Compound 1f withthiophene in B ring position can not be separated from the mixture of ifand a Grignard reagent coupling by-product3,4,5,3′,4′,5′-hexamethoxybiphenyl using flash column. So an alternativemethod was used to prepare 1f: Weinreb amide 38f was converted into itscorresponding aldehyde which was further reacted with3,4,5-trimethoxyphenylmagnesium bromide to afford the alcohol 40f, whichcan be easily separated from 3,4,5,3′,4′,5′-hexamethoxybiphenyl usingflash column chromatography. Oxidation with pyridinium dichromate (PDC)or DMSO did not afford if from secondary alcohol 40f with good yields.But using Dess-Martin periodinane reagent as oxidant successfully formedthe desired ketone compound 1f. 1e and 1i were prepared from alcohols40e and 40i using a similar method. Compound 1g was obtained via acoupling reaction from piperidine 41g and 3,4,5-trimethoxybenzoic acid.

Benzene B Ring: Synthesis ofBiphenyl-3-yl(3,4,5-trimethoxyphenyl)methanone (1a) (FIG. 2)

N-Methoxy-N-methylbiphenyl-3-carboxamide (38a). To a mixture of 37a (5mmol), EDCI (6 mmol), HOBt (5 mmol) and NMM (11 mmol) in CH₂Cl₂ (50 mL)was added HNCH₃OCH₃HCl salt (5 mmol) and stirring continued at RT for 2h. The reaction mixture was diluted with CH₂Cl₂ (100 mL) andsequentially washed with water, satd. NaHCO₃, brine and dried overMgSO₄. The solvent was removed under reduced pressure to yield acolorless oil, which was used for next step (58.4%). MS (ESI) m/z 264.0(M+Na)⁺.

Biphenyl-3-yl(3,4,5-trimethoxyphenyl)methanone (1a). To a solution of38a (FIG. 2) (0.174 g, 0.72 mmol.) in 5 mL THF was added a THF solutionof 3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 1.08 mmol) at 0° C.The mixture was allowed to stir for 30 min and quenched with satd.NH₄Cl, extracted with ethyl ether, dried with MgSO₄. The solvent wasremoved under reduced pressure to yield a crude product, which waspurified by column chromatography to obtain pure compound 1a as a whitesolid (43.8%). ¹H NMR (CDCl₃) δ 8.02 (t, 1H), 7.84-7.74 (m, 2H),7.64-7.38 (m, 6H), 7.11 (s, 2H), 3.95 (s, 3H), 3.88 (s, 6H); MS (ESI)m/z 371.1 (M+Na)⁺.

Pyrimidine B ring:

Synthesis of (6-Phenylpyrimidin-4-yl)(3,4,5-trimethoxyphenyl)methanone(1b) (FIG. 2)

N-Methoxy-N-methyl-6-phenylpyrimidine-4-carboxamide (38b). To a mixtureof 37b (5 mmol), EDCI (6 mmol), HOBt (5 mmol) and NMM (11 mmol) inCH₂Cl₂ (50 mL) was added HNCH₃OCH₃HCl salt (5 mmol) and stirringcontinued at RT for overnight. The reaction mixture was diluted withCH₂Cl₂ (100 mL) and sequentially washed with water, satd. NaHCO₃, brineand dried over MgSO₄. The solvent was removed under reduced pressure toyield a crude product, which was purified by column chromatography toobtain pure compound 38b as a yellow solid (62.3%). ¹H NMR (CDCl₃) δ9.28 (s, 1H), 8.14-8.06 (m, 2H), 7.96 (br, s, 1H), 7.54-7.50 (m, 3H),5.35 (br, t, 1H), 4.81 (br, t, 1H), 4.52 (dd, 1H, J=8.7 Hz, J=10.2 Hz),3.79 (s, 3H), 3.42 (s, 3H); MS (ESI) m/z 266.0 (M+Na)⁺.

(6-Phenylpyrinaidin-4-yl)(3,4,5-tritnethoxyphenyl)methanone (1b). To asolution of 38b (0.243 g, 1 mmol.) in 5 mL THF was added a THF solutionof 3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 5.6 mL, 1.4 mmol) at0° C. The mixture was allowed to stir for 30 min and quenched with satd.NH₄Cl, extracted with ethyl ether, dried with MgSO₄. The solvent wasremoved under reduced pressure to yield a crude product, which waspurified by column chromatography to obtain pure compound 1b (52.3%). ¹HNMR (CDCl₃) δ 9.40 (d, 1H, J=1.5 Hz), 8.29 (d, 1H, J=1.5 Hz), 8.22-8.18,7.57-7.54 (m, 5H), 7.46 (s, 2H), 3.96 (s, 3H), 3.91 (s, 6H); MS (ESI)m/z 351.1 (M+H)⁺.

Pyridine B Ring: Synthesis of(6-Phenylpyridin-2-yl)(3,4,5-trimethoxyphenyl)methanone (1c) (FIG. 2)

N-Methoxy-N-methyl-6-phenylpicolinamide (38c). To a mixture of 37c (1.77mmol), EDCI (2.12 mmol), HOBt (1.86 mmol) and NMM (3.54 mmol) in CH₂Cl₂(20 mL) was added HNCH₃OCH₃HCl salt (1.86 mmol) and stirring continuedat RT for overnight. The reaction mixture was diluted with CH₂Cl₂ (40mL) and sequentially washed with water, satd. NaHCO₃, brine and driedover MgSO₄. The solvent was removed under reduced pressure to yield acrude product, which was purified by column chromatography to obtainpure compound 38c as a colorless oil (51.2%). ¹H NMR (CDCl₃) δ 8.02 (d,1H, J=7.0 Hz), 7.86-7.81 (m, 2H), 7.55 (br, 1H), 7.48 (t, 2H), 7.44-7.41(m, 1H), 3.82 (s, 3H), 3.44 (s, br, 3H); MS (ESI) m/z 265.0 (M+Na)⁺.

(6-Phenylpyridin-2-yl)(3,4,5-trimethoxyphenyl)methanone (1c). To asolution of 38c (0.210 g, 0.86 mmol.) in 5 mL THF was added a THFsolution of 3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 3.5 mL, 1.73mmol) at 0° C. The mixture was allowed to stir for 30 min and quenchedwith water, extracted with ethyl acetate and dried with MgSO₄. Thesolvent was removed under reduced pressure to yield a crude product,which was purified by column chromatography to obtain pure 1c as whiteneedle crystals (78%). ¹H NMR (CDCl₃) δ 8.10 (d, br, 2H), 8.02-8.00 (m,1H), 7.97-7.96 (m, 2H), 7.66 (s, 2H), 7.49-7.43 (m, 3H), 3.97 (s, 3H),3.89 (s, 6H); MS (ESI) m/z 372.6 (M+Na)⁺.

Furan B Ring: Synthesis of(5-Phenylfuran-2-yl)(3,4,5-trimethoxyphenyl)methanone (1d) (FIG. 2)

N-Methoxy-N-methyl-5-phenylfuran-2-carboxamide (38d). To a mixture of37d (10 mmol), EDCI (12 mmol), HOBt (11 mmol) and NMM (21 mmol) inCH₂Cl₂ (200 mL) was added HNCH₃OCH₃HCl salt (10.5 mmol) and stirringcontinued at RT for overnight. The reaction mixture was diluted withCH₂Cl₂ (200 mL) and sequentially washed with water, satd. NaHCO₃, brineand dried over MgSO₄. The solvent was removed under reduced pressure toyield a crude product, which was purified by column chromatography toobtain pure compound 38d. (95.2%). ¹H NMR (CDCl₃) δ 7.82 (d, 1H, J=7.0Hz), 7.46-7.43 (t, 2H), 7.37-7.34 (m, 1H), 7.25 (d, 1H, J=4.0 Hz), 6.78(d, 1H, J=4.0 Hz), 3.86 (s, 3H), 3.41 (s, 3H); MS (ESI) m/z 254.1(M+Na)⁺.

(5-Phenylfuran-2-yl)(3,4,5-trimethoxyphenyl)methanone (1d). To asolution of 38d (0.231 g, 1 mmol.) in 5 mL THF was added a THF solutionof 3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 4.0 mL, 2 mmol) at 0°C. The mixture was allowed to stir for 30 min and quenched with water,extracted with ethyl acetate and dried with MgSO₄. The solvent wasremoved under reduced pressure to yield a crude product, which waspurified by column chromatography to obtain pure compound 1d as whitecrystals (35.5%). ¹H NMR (CDCl₃) δ 7.85-7.82 (m, 1H), 7.48-7.36 (m, 4H),7.35 (s, 2H), 7.25 (d, 1 H, J=4.0 Hz), 6.86 (d, 1H, J=4.2 Hz), 3.96 (s,3H), 3.95 (s; 6H); MS (ESI) m/z 339.1 (M+H)⁺.

Thiazole B Ring: Synthesis of(2-Phenylthiazol-5-yl)(3,4,5-trimethoxyphenyl)methanone (1e) (FIG. 2)

(2-Phenylthiazol-5-yl)(3,4,5-trimethoxyphenyl)methanol (40e). To asolution of 2-phenylthiazole-5-carbaldehyde 38e (0.567 g, 3 mmol.) in 15mL THF was added a THF solution of3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 6.5 mL, 3.25 mmol) at 0°C. The mixture was allowed to stir for 30 min and quenched with satd.NH₄Cl, extracted with ethyl ether, dried with MgSO₄. The solvent wasremoved under reduced pressure to yield a crude product, which waspurified by column chromatography to obtain pure compound 40e (72.9%).¹H NMR (CDCl₃) δ 7.90 (m, 2H), 7.64 (s, 1H), 7.41 (m, 3H), 6.69 (s, br,2H), 6.04 (s, 1H), 3.86 (s, 6H), 3.85 (s, 3H), 1.57 (d, 1H, J=5.5 Hz);MS (ESI) m/z 358.1 (M+Na)⁺.

(2-Phenylthiazol-5-yl)(3,4,5-trimethoxyphenyl)methanone (1e). To asolution of 40e (0.357 g, 1 mmol.) in 40 mL anhydrous CH₂Cl₂ was addedDess-Martin reagent (0.848 g, 2 mmol). The mixture was allowed to stirfor 30 min and quenched with sat. Na₂S₂O₃ solution, extracted with ethylacetate and dried with MgSO₄. The solvent was removed under reducedpressure to yield a crude product, which was purified by columnchromatography to give pure compound 1e (80.1%). ¹H NMR (CDCl₃) δ 8.33(s, 1H), 8.04 (m, 2H), 7.51 (m, 3H), 7.18 (s, 2H), 3.96 (s, 3H), 3.93(s, 6H); MS (ESI) m/z 378.1 (M+H)⁺.

Thiophene B Ring: Synthesis of(5-Phenylthiophen-3-yl)(3,4,5-trimethoxyphenyl)methanone (10 (FIG. 2)

N-Methoxy-N-methyl-5-phenylthiophene-3-carboxamide (381). To a mixtureof 37f (2.5 mmol), EDCI (2.9 mmol), HOBt (2.6 mmol) and NMM (5.3 mmol)in CH₂Cl₂ (30 mL) was added HNCH₃OCH₃HCl salt (2.6 mmol) and stirringcontinued at RT for overnight. The reaction mixture was diluted withCH₂Cl₂ (20 mL) and sequentially washed with water, satd. NaHCO₃, brineand dried over MgSO₄. The solvent was removed under reduced pressure toyield a crude product, which was purified by column chromatography toobtain pure compound 38f. (90.8%). ¹H NMR (CDCl₃) δ 8.28 (d, 1H, J=1.5Hz), 7.69 (d, 1H, J=1.5 Hz), 7.64 (d, 2H, J=7.0 Hz), 7.44 (t, 2H, J=7.0Hz), 7.35-7.32 (m, 1H), 6.78 (d, 1H, J=4.0 Hz), 3.86 (s, 3H), 3.41 (s,3H); MS (ESI) m/z 270.0 (M+Na)⁺.

(5-Phenylthiophen-3-yl)(3,4,5-trimethoxyphenyl)methanol (400. At −78°C., to a solution of 38f (2.5 mmol) in 5 mL THF under argon protectionwas added a solution of LiAlH₄ in THF (1N, 1.42 mL) and stirringcontinued at 1 h at −20° C. The reaction mixture was placed on an icebath and quenched by 20% H₂SO₄ solution, extracted with ethyl acetateand dried over MgSO₄. The solvent was removed under reduced pressure andpurified by column chromatography to yield5-phenylthiophene-3-carbaldehyde (not shown) (84.8%). ¹H NMR (CDCl₃) δ9.98 (s, 1H), 8.04 (d, 1H, J=1.5 Hz), 7.86 (br, 1H), 7.61-7.58 (br, 2H),7.47-7.33 (m, 3H), 7.35-7.32 (m, 1H), 6.78 (d, 1H, J=4.0 Hz); MS (ESI)m/z 210.9 (M+Na)⁺. To a solution of 5-phenylthiophene-3-carbaldehyde(0.195 g, 1.04 mmol.) in 5 mL THF was added a THF solution of3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 2.3 mL, 1.14 mmol) at 0°C. The mixture was allowed to stir for 30 min and quenched with satd.NH₄Cl, extracted with ethyl ether, dried with MgSO₄. The solvent wasremoved under reduced pressure to yield a crude product, which waspurified by column chromatography to obtain pure compound 40f. (70.5%).¹H NMR (CDCl₃) δ 7.55-7.52 (m, 2H), 7.40-7.35 (m, 3H), 7.30 (br, 1H),7.20 (br, 1H), 6.72 (s, 2H), 6.01 (d, 1H, J=3.9 Hz), 3.86 (s, 6H), 3.85(s, 3H), 2.42 (d, 1H, J=3.9 Hz); MS (ESI) m/z 339.1 (M—OH)⁻.

(5-Phenylthiophen-3-yl)(3,4,5-trimethoxyphenyl)methanone (10. To asolution of 40f (0.260 g, 0.73 mmol.) in 20 mL anhydrous CH₂Cl₂ wasadded Dess-Martin reagent (0.465 g, 1.36 mmol). The mixture was allowedto stir for 30 min and quenched with sat. Na₂S₂O₃ solution, extractedwith ethyl acetate and dried with MgSO₄. The solvent was removed underreduced pressure to yield a crude product, which was purified by columnchromatography to give pure compound 1f as light yellow crystals(60.9%). ¹H NMR (CDCl₃) δ 7.97 (d, 1H, J=1.5 Hz), 7.82 (d, 1H, J=1.5Hz), 7.59-7.57 (m, 2H), 7.45-7.34 (m, 3H), 7.19 (s, 2H), 3.95 (s, 3H),3.93 (s, 6H); MS (ESI) m/z 355.1 (M+H)⁺.

Piperidine B Ring: Synthesis of(4-Phenylpiperidin-1-yl)(3,4,5-trimethoxyphenyl)methanone (1g) (FIG. 2)

(4-Phenylpiperidin-1-yl)(3,4,5-trimethoxyphenyl)methanone (1g). To amixture of 4-phenylpiperidine 41g (5 mmol), EDCI (6 mmol), HOBt (5.5mmol) and NMM (6 mmol) in CH₂Cl₂ (50 mL) was added3,4,5-trimethoxybenzoic acid (5.3 mmol) and stirring continued at RT forovernight. The reaction mixture was diluted with CH₂Cl₂ (100 mL) andsequentially washed with water, satd. NaHCO₃, brine and dried overMgSO₄. The solvent was removed under reduced pressure to yield a crudeproduct, which was purified by column chromatography to obtain purecompound 1g. (57.9%). ¹H NMR (CDCl₃) δ 7.35-7.21 (m, 5 H), 6.66 (s, 2H),4.84 (br, 1H), 3.95 (br, 1H), 3.88 (s, 6H), 3.86 (s, 3H), 3.20-2.87 (br,2 H), 2.85-2.74 (tt, 1H, J=3.6 Hz, J=15.6 Hz) 1.92 (br, 2H), 1.70 (br,2H); MS (ESI) m/z 378.1 (M+Na)⁺.

Isoxazole B Ring: Synthesis of(5-Phenylisoxazol-3-yl)(3,4,5-trimethoxyphenyl)methanone (11) (FIG. 2)

(5-Phenylisoxazol-3-yl)(3,4,5-trimethoxyphenyl)methanol (40i). To asolution of 5-phenylisoxazole-3-carbaldehyde 38i (0.365 g, 2.1 mmol) in15 mL THF was added a THF solution of3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 5.5 mL, 2.74 mmol) at 0°C. The mixture was allowed to stir for 30 min and quenched with satd.NH₄Cl, extracted with ethyl ether, dried with MgSO₄. The solvent wasremoved under reduced pressure to yield a crude product, which waspurified by column chromatography to obtain pure compound 40i as a whitesolid. (48.8%). ¹H NMR (CDCl₃) δ 7.78-7.77 (m, 2H), 7.48-7.46 (m, 3H),6.74 (s, 2H), 6.45 (s, 1H), 5.98 (d, 1H, J=3.5 Hz) 3.89 (s, 6H), 3.86(s, 3 H), 2.77 (d, 1H, J=3.5 Hz); MS (ESI) m/z 364.1 (M+Na)⁺.

(5-Phenylisoxazol-3-yl)(3,4,5-trimethoxyphenyl)methanone (11). To asolution of 40i (0.110 g, 0.73 mmol.) in 8 mL anhydrous CH₂Cl₂ was addedDess-Martin reagent (0.274 g, 0.645 mmol). The mixture was allowed tostir for 30 min and quenched with sat. Na₂S₂O₃ solution, extracted withethyl acetate and dried with MgSO₄. The solvent was removed underreduced pressure to yield a crude product, which was purified by columnchromatography to give pure compound 1i (70.1%). ¹H NMR (CDCl₃) δ7.87-7.85 (m, 2H), 7.72 (s, 2H), 7.53-7.49 (m, 3H), 7.05 (s, 1H), 7.82(d, 1H, J=1.5 Hz), 3.97 (s, 3H), 3.96 (s, 6H); MS (ESI) m/z 362.1(M+H)⁺.

Pyrazole B Ring: Synthesis of(3-Phenyl-1H-pyrazol-5-yl)(3,4,5-trimethoxyphenyl)methanone (1k) (FIG.2)

(3-Phenyl-1H-pyrazol-5-yl)(3,4,5-trimethoxyphenyl)methanone (1k) wasprepared using the same method as used of compound 1c from3-phenyl-1H-pyrazole-5-carboxylic acid. ¹H NMR (500 MHz, CDCl₃ δ 10.97(br, 1H), 7.77 (s, br, 2H), 7.48-7.38 (m, 5H), 7.14 (s, br, 1H), 3.96(s, 3H), 3.94 (s, 6H); MS (ESI) m/z 361.1 (M+Na)⁺, 337.0 (M—H)⁻.

Example 2 Synthesis of Compounds of this Invention Having Different YLinkers

The compounds of this invention possess different Y linkers. Suchcompounds, with different Y linkers, were synthesized according to FIGS.3 and 4.

Compound 1h was synthesized from2-phenyl-4,5-dihydro-thiazole-4-carboxylic acid 42a through three stepsdescribed before (Lu, Y.; Wang, Z.; Li, C. M.; Chen, J.; Dalton, J. T.;Li, W.; Miller, D. D., Synthesis, in vitro structure-activityrelationship, and in vivo studies of 2-arylthiazolidine-4-carboxylicacid amides as anticancer agents. Bioorg Med Chem 2010, 18, (2), 477-95which is incorporated herein by reference in its entirely). 1h wasconverted to oxime isomers 2e-cis,trans and 2f-cis,trans upon reactionwith hydroxylamines, NH₂OH or NH₂OCH₃. Assignments were made on thebasis of chemical and spectral data as described infra. An improvedBeckmann rearrangement readily produced the rearranged amides 2g and 2hfrom the two geometric stereoisomers 2e-cis and 2e-trans via theirreaction with tosyl chloride and subsequent basic aluminum oxide column.Hydrazide derivatives 2d-cis and 2d-trans were prepared by mixing 1hwith hydrazine hydrate in ethanol and refluxing for 24 h. Acrylonitriles2c-trans,cis were obtained from Wittig reaction of 1h with diethylcyanomethylphosphonate. Cyanoimine 2j was prepared using the procedureas by described by Cuccia (Cuccia, S. J.; Fleming, L. B.; France, D. J.,A novel and efficient synthesis of 4-phenyl-2-chloropyrimidines fromacetophenone cyanoimines. Synthetic Communications 2002, 32, (19),3011-3018., incorporated herein by reference in its entirely). Thecarbonyl group in compound 1h was also reduced to a secondary alcohol 2bor converted to an alkene (2a) as illustrated in FIG. 3.

Attempts to remove the carbonyl group between B and C rings in 1h,resulted in the formation of compound 2i as shown in FIG. 4. Introducingcis- and trans-double bonds into the carbonyl position formed compounds(3a and 3b), which were synthesized from a Wittig reaction with2-phenylthiazole-4-carbaldehyde. The sulfide compound 4a, sulfone 4b andsulfoxide 4c were prepared using 3-aminobiphenyl as starting materialthrough an initial Sandmeyer reaction to yield carbonodithioate 52a,followed by CuI catalyzed coupling reaction and m-CPBA oxidation.Sulfonamide linked compound 4d was prepared from reaction of3-biphenylsulfonyl chloride with 3,4,5-trimethoxyaniline in the presenceof NEt₃ in DMF.

Synthesis of (2-Phenyl-thiazol-4-yl)-(3,4,5-trimethoxy-phenyl)-methanone(1h) [FIG. 3]

(2-Phenyl-thiazol-4-yl)-(3,4,5-trimethoxy-phenyl)-methanone (1h). Amixture of 2-phenyl-4,5-dihydrothiazole-4-carboxylic acid (5 mmol), EDCI(6 mmol) and HOBt (5 mmol) in CH₂Cl₂ (50 mL) was stirred for 10 min. Tothis solution, NMM (5 mmol) and HNCH₃OCH₃ (5 mmol) were added andstirring continued at RT for 6-8 h. The reaction mixture was dilutedwith CH₂Cl₂ (100 mL) and sequentially washed with water, satd. NaHCO₃,brine and dried over MgSO₄. The solvent was removed under reducedpressure to yield a crude product, which was purified by columnchromatography to get 2-phenyl-4,5-dihydrothiazole-4-carboxylic acidmethoxymethylamide. A solution of2-phenyl-4,5-dihydrothiazole-4-carboxylic acid methoxymethylamide (1equiv) in CH₂Cl₂ was cooled to 0° C., and distilled DBU (2 equiv) wasadded. Bromotrichloromethane (1.7 equiv) was then introduced dropwisevia syringe over 10 min. The reaction mixtures were allowed to warm toRT and stirred overnight. Upon washing with satd. aqueous NH₄Cl (2×50mL), the aqueous phase was extracted with EtOAc (3×50 mL). The combinedorganic layers were dried on MgSO₄, filtered and concentrated in vacuo.The residue was purified by flash chromatography as needed providing2-phenyl-thiazole-4-carboxylic acid methoxymethylamide (73.6%). ¹H NMR(300 MHz, CDCl₃) δ 8.01 (s, 1H), 7.99-7.96 (m, 2H), 7.47-7.44 (m, 3H),3.88 (s, 3H), 3.49 (s, 3H). MS (ESI) m/z 271.0 (M+Na)⁺. To a solution of3,4,5-trimethoxyphenylmagnesium bromide (0.5 N, 3 mL) in 2 mL THF wascharged a solution of 2-phenyl-thiazole-4-carboxylic acidmethoxymethylamide (1 mmol) in 3 mL THF at 0° C. The mixtures werestirred for 30 min until amides disappeared on TLC plates. The reactionmixture was quenched with satd. NH₄Cl, extracted with ethyl ether, driedwith MgSO₄. The solvent was removed under reduced pressure to yield acrude product, which was purified by column chromatography to obtainpure compound 1h. Yield: 27.3%. ¹H NMR (300 MHz, CDCl₃) δ 8.29 (s, 1H),8.03 (q, 2H), 7.80 (s, 2H), 7.49-7.47 (m, 3H), 3.96 (s, 6H), 3.97 (s,3H). MS (ESI) m/z 378.1 (M+Na)⁺.

Synthesis of4-(2-Methyl-1-(3,4,5-trimethoxyphenyl)prop-1-enyl)-2-phenylthiazole (2a)[FIG. 3]

4-(2-Methyl-1-(3,4,5-trimethoxyphenyl)prop-1-enyl)-2-phenylthiazole (2a)[FIG. 3]. At −78° C., to a solution of 223 mg isopropyltriphenylphosphonium iodide (0.52 mmol) in 5 mL of THF was addeddropwise 0.4 mL of 1.6 N n-BuLi in hexane under Ar₂ protection. And themixture was stirred at 0° C. for 40 min. A solution of 140 mg (0.39mmol) of 1h in 5 mL of THF was added dropwise at 0° C., and the mixturewas stirred for 1h at RT. The reaction mixture was treated withsaturated NH₄Cl solution. After a conventional workup, columnchromatography (silica gel, petroleum ether/ethyl acetate) gave compound2a (86 mg, 57.3%). ¹H NMR (300 MHz, CDCl₃) δ 7.98-7.97 (m, 2H),7.45-7.40 (m, 3H), 6.77 (s, 1H), 6.48 (s, 2H), 3.86 (s, 3H), 3.82 (s,6H), 2.15 (s, 3H), 1.81 (s, 3H). MS (ESI) m/z 404.1 (M+Na)⁺.

Synthesis of (2-Phenylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanol(2b)[FIG. 3]

2-Phenyl-4,5-dihydrothiazole-4-carboxylic acid (42a). Benzonitrile (40mmol) was combined with L-cysteine (45 mmol) in 100 mL of 1:1 MeOH/pH6.4 phosphate buffer solution. The reaction was stirred at 40° C. for 3days. The precipitate was removed by filtration, and MeOH was removedusing rotary evaporation. To the remaining solution was added 1M HCl toadjust to pH=2 under 0° C. The resulting precipitate was filtered toyield a white solid 2-phenyl-4,5-dihydrothiazole-4-carboxylic acid 42a,which was used directly to next step without purification.

2-Phenylthiazole-4-carbaldehyde (42b). At −78° C., to a solution of2-phenyl-thiazole-4-carboxylic acid methoxymethylamide (1 equiv) in THFwas added LiAlH₄ (1 equiv, 1 N in THF) and stirring for 1h at −20° C.The reaction mixture was placed on an ice bath and quenched by 20% H₂SO₄solution, extracted with ethyl acetate and dried over MgSO₄. The solventwas removed under reduced pressure and purified by column chromatographyto yield 42b (45.8%). ¹H NMR (300 MHz, CDCl₃) δ 10.1 (s, 1H), 8.17 (s,1H), 8.02-8.00 (m, 2H), 7.50-7.48 (m, 3H). MS (ESI) m/z 244.1(M+Na+MeOH)⁺.

(2-Phenylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanol (2b) [FIG. 3]. At0° C., to a solution of 104 mg of 42b (0.55 mmol, 1 eq.) in 6 mL THF wasadded 3,4,5-trimethoxyphenylmagnesium bromide (0.5 N in THF, 2.9 mL).The mixtures were stirred for 30 min until aldehyde disappeared on TLCplates. The reaction mixture was quenched with satd. NH₄Cl, extractedwith ethyl ether, dried with MgSO₄. The solvent was removed underreduced pressure to yield a crude product, which was purified by columnchromatography to obtain pure compound (2b). ¹H NMR (300 MHz, CDCl₃) δ7.95-7.92 (m, 2H), 7.44-7.43 (m, 4H), 6.97 (s, 1H), 6.76 (s, 2H), 5.93(d, 1H, J=3.6 Hz), 3.86 (s, 9H). MS (ESI) m/z 402.1 (M+Na)⁺.

Synthesis of(Z)-3-(2-phenylthiazol-4-yl)-3-(3,4,5-trimethoxyphenyl)acrylonitrile(2c-trans) and(E)-3-(2-phenylthiazol-4-yl)-3-(3,4,5-trimethoxyphenypacrylonitrile(2c-cis) [FIG. 3]

(Z)-3-(2-phenylthiazol-4-yl)-3-(3,4,5-trimethoxyphenypacrylonitrile(2c-trans). To a solution of 0.4 mL of 2.5 N n-BuLi in hexane and 10 mLof THF was added dropwise a solution of 177 mg (1 mmol) of diethylcyanomethylphosphonate in 5 mL of THF at 0° C. under Ar₂. The ice bathwas removed, and the mixture was stirred at 25° C. for 40 min. Asolution of 200 mg (0.56 mmol) of 1h in 10 mL of THF was added dropwiseat 0° C., and the mixture was stirred for 1h at RT. The reaction mixturewas treated with saturated NH₄Cl solution. After a conventional workup,column chromatography (silica gel, petroleum ether/ethyl acetate) gavecompounds 2c-trans (83 mg) and 2c-cis (76 mg). ¹H NMR (300 MHz, CDCl₃) δ8.01-7.99 (m, 2H), 7.44-7.40 (m, 3H), 7.21 (s, 1H), 6.74 (s, 2H), 6.67(s, 1H), 3.93 (s, 3H), 3.89 (s, 6H). MS (ESI) m/z 401.1 (M+Na)⁺.

(E)-3-(2-phenylthiazol-4-yl)-3-(3,4,5-trimethoxyphenypacrylonitrile(2c-cis). ¹H NMR (300 MHz, CDCl₃) δ 8.07-8.05 (m, 2H), 7.49-7.46 (m,4H), 6.66 (s, 2H), 5.64 (s, 1H), 3.91 (s, 3H), 3.86 (s, 6H). MS (ESI)m/z 401.1 (M+

Synthesis of(Z)-4-(hydrazono(3,4,5-trimethoxyphenyl)methyl)-2-phenylthiazole(2d-cis) and(E)-4-(hydrazono(3,4,5-trimethoxyphenyl)methyl)-2-phenylthiazole(2d-trans) [FIG. 3]

(Z)-4-(hydrazono(3,4,5-trimethoxyphenyl)methyl)-2-phenylthiazole(2d-cis). To a mixture of 1h (230 mg, 0.65 mmol) in 3 mL CH₂Cl₂ and 3 mLethanol was added hydrazine hydrate (2 mL). Then the mixture wasrefluxed for overnight. After completion of the reaction, the residuewas absorbed on silica gel and purified by column chromatography to givecompounds 2d-cis (80 mg) and 2d-trans (56 mg). ¹H NMR (300 MHz, CDCl₃) δ8.01-7.98 (m, 2H), 7.49-7.46 (m, 5H), 7.33 (s, 1H), 6.82 (s, 2H), 3.87(s, 3H), 3.85 (s, 6H). MS (ESI) m/z 370.1 (M+H)⁺.

(E)-4-(hydrazono(3,4,5-trimethoxyphenyl)methyl)-2-phenylthiazole(2d-trans). ¹H NMR (300 MHz, CDCl₃) δ 8.04-8.01 (m, 2H), 7.44-7.40 (m,3H), 6.95 (s, 1H), 6.65 (s, 2H), 5.62 (s, 2H), 3.93 (s, 3H), 3.87 (s,6H). MS (ESI) m/z 370.1 (M+H)⁺.

Synthesis of (Z)-(2-Phenylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanoneoxime (2e-cis) and(E)-(2-Phenylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone oxime(2e-trans) [FIG. 3]

(Z)-(2-Phenylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone oxime(2e-cis) To a suspension of 1h (210 mg, 0.59 mmol) in 10 mL ethanol wasadded an aqueous solution (2 mL) of hydroxylamine hydrochloride (127 mg,1.83 mmol). Then 2 mL 1 N NaOH was added dropwise to the reactionmixture and the mixture was stirred at 55° C. for 3 h. After completionof the reaction, the residue was absorbed on silica gel and purified bycolumn chromatography to give compounds 2e-cis (85 mg) and 2e-trans (50mg). ¹H NMR (300 MHz, DMSO-d₆) δ 11.95 (s, 1H), 8.35 (s, 1H), 7.91-7.89(m, 2H), 7.50-7.44 (br, 3H), 6.85 (s, 2H), 3.73 (s, 6H), 3.70 (s, 3H).MS (ESI) m/z 393.1 (M+Na)⁺; 368.9 (M−H)⁻.

(E)-(2-Phenylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone oxime2e-trans). ¹H NMR (300 MHz, DMSO-d₆) δ 11.49 (s, 1H), 7.92-7.89 (m, 2H),7.64 (s, 1H), 7.51-7.49 (m, 3H), 7.34 (s, 1H), 6.75 (s, 2H), 3.75 (s,6H), 3.72 (s, 3H). MS (ESI) m/z 393.1 (M+Na)⁺; 368.9 (M−H)⁻.

Synthesis of (Z)-(2-Phenylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanoneO-methyl oxime (2f-cis) and(E)-(2-Phenylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone O-methyloxime (2f-trans) [FIG. 3]

(Z)-(2-Phenylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone O-methyloxime (2f-cis). To a suspension of 1h (110 mg, 0.59 mmol) in 10 mLpyridine was added O-methylhydroxylamine hydrochloride (52 mg, 0.63mmol) and the mixture was stirred at 60° C. for overnight. The reactionwas quenched with 1 N HCl solution, extracted with ethyl acetate anddried with MgSO₄. The solvent was removed under reduced pressure toyield a crude product, which was purified by column chromatography togive pure compounds 2f-cis (41 mg) and 2f-trans (33 mg). ¹H NMR (500MHz, CDCl₃) δ 8.13 (s, 1H), 7.96-7.94 (m, 2H), 7.45-7.44 (m, 3H), 6.94(s, 2H), 4.13 (s, 3H), 3.91 (s, 6H), 3.88 (s, 3H). MS (ESI) m/z 407.2(M+Na)⁺.

(E)-(2-Phenylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone O-methyloxime (2f-trans). ¹H NMR (500 MHz, CDCl₃) δ 8.00-7.98 (m, 2H), 7.44-7.43(m, 3H), 7.28 (s, 1H), 6.70 (s, 2H), 4.08 (s, 3H), 3.91 (s, 6H), 3.85(s, 3H). MS (ESI) m/z 407.0 (M+Na)⁺.

Synthesis of 2-Phenyl-N-(3,4,5-trimethoxyphenyl)thiazole-4-carboxamide(2g) [FIG. 3]

2-Phenyl-N-(3,4,5-trimethoxyphenyl)thiazole-4-carboxamide (2g). To asolution of 2e-cis (21 mg, 0.06 mmol) in 5 mL CH₂Cl₂ was addedp-toluenesulfonyl chloride (23 mg, 0.12 mmol) and NaH (5 mg, 60% inlight mineral oil). Then the reaction mixture was stirred for 20 min.After completion of the reaction, the residue was absorbed on silica geland purified by Al₂O₃ column chromatography to give compound 2g (15 mg).¹H NMR (300 MHz, CDCl₃) δ 9.22 (s, 1H), 8.19 (s, 1H), 8.02-7.99 (m, 2H),7.52-7.50 (m, 3H), 7.07 (s, 2 H), 3.92 (s, 6H), 3.85 (s, 3H). MS (ESI)m/z 371.1 (M+H)⁺.

Synthesis of 3,4,5-Trimethoxy-N-(2-phenylthiazol-4-yl)benzamide (2h)[FIG. 3]

3,4,5-Trimethoxy-N-(2-phenylthiazol-4-yl)benzamide (2h). To a solutionof 2e-trans (26 mg, 0.07 mmol) in 5 mL CH₂Cl₂ was addedp-toluenesulfonyl chloride (27 mg, 0.14 mmol) and NaH (5 mg, 60% inlight mineral oil). Then the reaction mixture was stirred for 20 min.After completion of the reaction, the residue was absorbed on silica geland purified by Al₂O₃ column chromatography to give compound 2h (15 mg).¹H NMR (300 MHz, CDCl₃) δ 8.88 (s, 1H), 7.94-7.91 (m, 2H), 7.83 (s, 1H),7.48-7.46 (m, 3H), 7.18 (s, 2 H), 3.97 (s, 6H), 3.94 (s, 3H). MS (ESI)m/z 393.1 (M+Na)⁺.

Synthesis ofN-((2-phenylthiazol-4-yl)(3,4,5-trimethoxyphenypmethylene)cyanamide (2j)[FIG. 3]

N-β2-phenylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methylene)cyanamide(2j). 100 mg of 1h (0.28 mmol, 1 eq.) was dissolved in 10 mL methylenechloride. Titanium tetrachloride in methylene chloride (1.0 N, 0.7 mL,2.5 eq.) was added dropwise at 0° C. and stirred for 30 min.Bis-trimethylsilylcarbodiimide (2.4 eq.) in 2 mL methylene chloride wasadded and the reaction stirred overnight protected from air andmoisture. The reaction was treated with ice-water mixture followed byextraction with methylene chloride. The organic phase was dried overmagnesium sulfate, filtered through celite and concentrated to give thecrude acetophenone cyanoimines which were purified by flash column asisomers with a ratio of 3:7. ¹H NMR (300 MHz, CDCl₃) δ 8.72 (br, 0.3H),8.63 (s, 0.7H), 8.09-8.07 (m, 1.4H), 7.99 (br, 0.6H), 7.58-7.56 (br,3H), 7.26 (s, 1.4H), 7.18 (s, 0.6H), 3.84, 3.83 (s, s, 6H), 3.82 (s,3H). MS (ESI) m/z 402.1 (M+Na)⁺.

Synthesis ofN-((4-hydroxy-3,5-dimethoxyphenyl)(2-phenylthiazol-4-yl)methylene)cyanamide(32)

N-((4-hydroxy-3,5-dimethoxyphenyl)(2-phenylthiazol-4-yl)methylene)cyanamide(32) was obtained as a by-product from synthesis of 2j. ¹H NMR (500 MHz,CDCl₃) δ 8.23 (s, 1 H), 8.02 (m, 2H), 7.92 (s, 2H), 7.55 (m, 3H), 6.02(s, 1H), 3.99 (s, 6H). MS (ESI) m/z 364.1 (M+H)⁺.

Synthesis of (Z)-2-Phenyl-4-(3,4,5-trimethoxystyryl)thiazole (3a) and(E)-2-Phenyl-4-(3,4,5-trimethoxystyryl)thiazole (3b) [FIG. 4]

(Z)-2-Phenyl-4-(3,4,5-trimethoxystyryl)thiazole (3a). Triphenylphosphine(3.41 g, 13 mmol) was added to a solution of5-(bromomethyl)-1,2,3-trimethoxybenzene (2.61 g, 10 mmol) in dry THF (30mL). The mixture was refluxed with stirring for 6 h. The resulting whitesolid was filtered and washed with ether/hexane to afford the product3,4,5-trimethoxybenzyltriphenylphosphonium bromide in 96.4% yield. ¹HNMR (500 MHz, CDCl₃) δ 7.77-7.73, 7.65-7.61 (m, 15H), 6.44 (d, 2H,J=1.5Hz), 5.37 (d, 2H, J=14Hz), 3.76 (s, 3H), 3.51 (d, 6H); MS (ESI) m/z443.1 (M—Brr. At −78° C., n-BuLi (0.42 mL, 2.5 N in hexane) was added toa solution of 3,4,5-trimethoxybenzyltriphenylphosphonium bromide (500mg, 0.96 mmol) in 10 mL THF. After stirring at RT for 2 h, aldehyde 42b(109 mg, 0.58 mmol) in 3 mL THF was charged and stirred for 30 min. Thereaction mixture was treated with saturated NH₄Cl solution. After aconventional workup, column chromatography (silica gel, petroleumether/ethyl acetate) gave compounds 3a (57 mg) and 3b (99 mg). ¹H NMR(500 MHz, CDCl₃) δ 7.90-7.89 (m, 2H), 7.42-7.40 (m, 3H), 7.07 (s, 1H),6.71 (s, 2H), 6.66 (s, 1H), 3.87 (s, 6H), 3.75 (s, 3H); MS (ESI) m/z376.1 (M+Na)⁺.

(E)-2-Phenyl-4-(3,4,5-trimethoxystyryl)thiazole (3b). ¹H NMR (500 MHz,CDCl₃) δ 8.03-8.01 (m, 2H), 7.52 (d, 1H, J=16 Hz), 7.47-7.44 (m, 3H),7.16 (s, 1H), 7.05 (d, 1H, J=16 Hz), 6.79 (s, 2H), 3.92 (s, 6H), 3.88(s, 3H). MS (ESI) m/z 354.1 (M+H)⁺.

Synthesis of Biphenyl-3-yl(3,4,5-trimethoxyphenyl)sulfane (4a),3-(3,4,5-Trimethoxyphenylsulfonyl)biphenyl (4b) and3-(3,4,5-Trimethoxyphenylsulfinyl)biphenyl (4c) [FIG. 4]

S-Biphenyl-3-yl O-ethyl carbonodithioate (52a). To a solution of 1equiv. of biphenyl-3-amine (1 g, 5.92 mmol) in water (7.3 mL) at 0° C.was added concentrated hydrochloric acid (1 mL). A cold solution of 1.1equiv. of sodium nitrite (450 mg, 6.5 mmol) in water (3 mL) was addedslowly and stirred for 15 min. The cold diazonium solution was addedslowly to a solution of 1.3 equiv. of potassium ethyl xanthate (1.16 g,1.3 mmol) in water (1.3 mL) at 45° C. The reaction mixture was stirredfor an additional 30 min at 45° C. and then cooled to RT. The reactionmixture was extracted with diethyl ether (3×50 mL). The combined organicextracts were washed with 1 N NaOH solution (100 mL), water (3×50 mL),brine (50 mL), dried over MgSO₄, filtered and evaporated under reducedpressure. The resulting crude xanthate 52a was used directly in the nextstep without further purification. MS (ESI) m/z 275.0 (M+H)⁺.

Biphenyl-3-yl(3,4,5-trimethoxyphenyl)sulfane (4a). To a solution of 52a(1.1 g, crude compound) in ethanol (8 mL) was added potassium hydroxide(2.1 g, 12 mL) and heated to reflux for overnight. The solution wascooled to RT and the ethanol was evaporated under reduced pressure. Theresidue was dissolved in water and washed with diethyl ether (10 mL).The aqueous layer was acidified with 2 N HCl and extracted with diethylether (3×50 mL). The organic extracts were washed with water (50 mL),brine (50 mL), dried over MgSO₄, filtered and evaporated under reducedpressure to afford 0.85 g (77.3%) of crude biphenyl-3-thiol product(overall, 3 steps). Into a round-bottomed flask, stirred magnetically,were placed 0.1 g (1.04 mmol) of sodium tert-butoxide and 83 mg ofcopper iodide (0.43 mmol). After the reaction vessel was sealed, 0.13 g(0.71 mmol) of 4-methoxybenzenethiol and 0.19 g (0.65 mmol) of5-iodo-1,2,3-trimethoxybenzene in 3.0 mL of toluene were injectedthrough the septum. The reaction mixture was heated for overnight at110° C. Purification was performed by flash chromatography, and anamorphous solid was obtained (40% yield). ¹H NMR (500 MHz, CDCl₃) δ7.54-7.52 (m, 3H), 7.44-7.41 (m, 3H), 7.37-7.33 (m, 2H), 7.23 (s, br,1H), 6.69 (s, 2H), 3.86 (s, 3H), 3.80 (s, 6H). MS (ESI) m/z 353.2(M+H)⁺.

3-(3,4,5-Trimethoxyphenylsulfonyl)biphenyl (4b). To a solution of 60 mg(0.17 mmol) of compound 4a and 5 mL of dichloromethane was added veryslowly 2 equiv. of m-CPBA over 3 h. Sulfoxide formation was monitored bythin-layer chromatography. Purification was performed with a flashchromatographic column, and an amorphous powder of (4b) was obtained(73% yield). ¹H NMR (500 MHz, CDCl₃) δ 8.14 (br, 1H), 7.89 (d, 1H), 7.78(d, 1H), 7.59-7.56 (m, 3H), 7.49-7.39 (m, 3H), 7.19 (s, 2H), 3.89 (s,6H), 3.87 (s, 3 H). MS (ESI) m/z 385.0 (M+Na)⁺.

3-(3,4,5-Trimethoxyphenylsulfinyl)biphenyl (4c). At 0° C., to a solutionof 500 mg (1.42 mmol) of compound (4a) and 5 mL of dichloromethane wasadded very slowly 1 equiv. of m-CPBA over 3 h. Sulfoxide formation wasmonitored by thin-layer chromatography. Purification was performed witha flash chromatographic column, and an amorphous powder of (4c) wasobtained (87% yield). ¹H NMR (500 MHz, CDCl₃) δ 7.92 (br, 1H), 7.71 (d,2H), 7.62-7.60 (m, 3H), 7.58-7.40 (m, 4H), 6.94 (s, 2H), 3.79 (s, 3H),3.74 (s, 6H). MS (ESI) m/z 369.1 (M+H)⁺.

Synthesis of N-(3,4,5-trimethoxyphenyl)biphenyl-3-sulfonamide (4d) [FIG.4]

N-(3,4,5-Trimethoxyphenyl)biphenyl-3-sulfonamide (4d). A mixture of 65mg of biphenyl-3-sulfonyl chloride (0.25 mmol), 44 mg of3,4,5-trimethoxyaniline (0.24 mmol), and 0.3 mmol of triethylamine in 5mL DMF was stirred overnight. The reaction mixture was treated withwater and extracted with ethyl acetate. After a conventional workup,column chromatography (silica gel, petroleum ether/ethyl acetate) gave88 mg compounds (4d) (91.7%). ¹H NMR (500 MHz, CDCl₃) δ 7.96 (t, 1H,J=1.8 Hz), 7.81-7.74 (m, 2H), 7.57-7.40 (m, 6H), 6.33 (s, 2H), 3.86 (s,3H), 3.80 (s, 6H). MS (ESI) m/z 422.1 (M+Na)⁺.

2-Phenyl-4-(3,4,5-trimethoxyphenyl)thiazole (2i) [FIG. 4]

2-Phenyl-4-(3,4,5-trimethoxyphenyl)thiazole (21). Bromine (160 mg, 1mmol) was added dropwise to a stirred solution of an1-(3,4,5-trimethoxyphenyl)ethanone (210 mg, 1 mmol) in ethanol (30 mL)and the solution was stirred at 0° C. for 1 h and then poured into waterto form a precipitate. This was recrystallized from ethanol to givebromoacetophenone (70%) and used directly for next step. A mixture ofbromoacetophenone (288 mg, 1 mmol) and benzothioamide (137 mg, 1 mmol)in ethanol was refluxed for 1 h. The reaction mixture was concentratedin vacuo and purified with flash column to give 2i (167 mg, 51.1%). ¹HNMR (500 MHz, CDCl₃) δ 8.05-8.03 (m, 2H), 7.48-7.44 (m, 3H), 7.41 (s, 1H), 7.22 (s, 2H), 3.97 (s, 6H), 3.89 (s, 3H). MS (ESI) m/z 350.1(M+Na)⁺.

Example 3 Synthesis of Methoxy Benzoyl Thiazole Compounds HavingDifferent “A” Rings and/or Substituted “A” Ring

The compounds of this invention possess different substituted orunsubstituted A rings such as benzyl or indolyl. Such compounds weresynthesized according to FIGS. 5 and 6.

Hydroxyl and aminomethyl were introduced at the para-position of thephenyl A-ring, as well as the phenyl was replaced with 5-indolyl and2-indolyl rings. Weinreb amides 57a, 61a, 65a, and 67a were prepared bythe procedure presented in FIG. 5 using aryl nitriles as startingmaterials. 2-Cyano-indole 60a was prepared according to a standardprocedure (Pletnev, A. A.; Tian, Q.; Larock, R. C., Carbopalladation ofnitriles: synthesis of 2,3-diarylindenones and polycyclic aromaticketones by the Pd-catalyzed annulation of alkynes and bicyclic alkenesby 2-iodoarenenitriles. J Org Chem 2002, 67, (26), 9276-87. incorporatedherin by reference in its entirely). Protections of hydroxyl (TBDMSC1),indolyl (PhSO₂Cl) and amino (Boc₂O) groups were used in preparations.Deprotection of TBDMS and oxidation from thiazoline (58a) to thiazole(21) took place in one-step using TBAF/THF solution. Thisthiazoline-thiazole oxidation takes place spontaneously in the reactionof thiazoline Weinreb amide and Grignard reagent. The same phenomena isobserved during preparation of the indole compounds 62a and 66a.

Compound 62a was separated as a pure thiazole compound after reactionwith 3,4,5-trimethoxphenyllithium without the need for furtheroxidation. Compound 66a was obtained by removing the phenylsulfonylprotecting groups in hot NaOH ethanol solution. para-OH and NH₂ on the Aring of 2l and 2r were obtained by similar Grignard reactions from theWeinreb amides 58a and 68a. Compound 2r was further converted to the HClsalt (2r-HCl) and the HCl salt of monomethyl amine 2s-HC1 using NaH/MeIconditions and dimethylamine 2u under HCHO/NaBH₃CN conditions.

Substituted A Ring: Synthesis of(2-(4-Hydroxyphenyl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (2l)[FIG. 5]

(R)-2-(4-Hydroxyphenyl)-N-methoxy-N-methyl-4,5-dihydrothiazole-4-carboxamide(57a) was synthesized using the same method as used for 38d.Quantitative yield. ¹H NMR (500 MHz, CDCl₃) δ 7.56 (d, 2H, J=8.5 Hz),6.84 (br, 1, H), 6.73 (d, 2H, J=8.5 Hz), 5.64 (t, br, 1H), 3.87 (s, 3H),3.30 (s, 3H). MS (ESI) m/z 289.0 (M+Na)⁺, 264.9 (M−H)⁻.

(R)-(2-(4-(tert-Butyldimethylsilyloxy)phenyl)-4,5-dihydrothiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(58a) was synthesized using the same method as used for (35a)—seeExample 1. 67.0% yield. ¹H NMR (300 MHz, CDCl₃) δ 7.73 (d, 2H, J=8.7Hz), 7.61 (s, 2H), 6.83 (d, 2H, J=8.7 Hz), 5.95 (dd, 1H, J=8.1 Hz, 9.0Hz), 4.09, (dd, 1H, J=7.8 Hz, 11.1 Hz), 3.95 (s, 3H), 3.94 (s, 6H), 3.55(dd, 1H, J=9.3 Hz, 11.1 Hz), 0.97 (s, 9H), 0.19 (s, 6H). MS (ESI) m/z510.4 (M+Na)⁺, 486.0 (M−H)⁻.

(2-(4-Hydroxyphenyl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (21).At 0° C., to a solution of 58a (0.2 mmol) in 5 mL CH₂Cl₂ was added asolution of tetrabutylammonium fluoride in THF (1 N, 0.6 mmol) andstirred at RT for around 14 h until reaction was finished by TLCmonitor. 67.0% yield. ¹H NMR (500 MHz, DMSO-d₆) δ 10.1 (s, 1H), 8.51 (s,1H), 7.85 (d, 2H, J=8.50 Hz), 7.62 (s, 2H), 6.91 (d, 2H, J=8.5 Hz), 3.86(s, 6H), 3.79 (s, 3H). MS (ESI) m/z 394.1 (M+Na)⁺, 369.9 (M−H)⁻.

(2-(4-(Aminomethyl)phenypthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanonehydrochloride (2r or 2r-HCl) [FIG. 5]

(R)-tert-Butyl4-(4-(methoxy(methypcarbamoyl)-4,5-dihydrothiazol-2-yl)benzyl carbamate(67a). 4-(Aminomethyl)benzonitrile (25.09 g, 0.149 mol) and L-cysteine(18.1 g, 0.149 mol) were suspended in 500 mL MeOH and pH 6.4 buffersolutions (1:1) and stirred for 3 days at RT. Triethylamine (30 mL) wasadded to the mixture and Boc₂O (68 g, 0.31 mol) was added to thismixture and stirred for 2 h. The solvents were removed and filtered toyield white solid(R)-2-(4-((tert-butoxycarbonylamino)methyl)phenyl)-4,5-dihydrothiazole-4-carboxylicacid (38.4 g, 76.8%). Compound 67a was obtained from this acid followingthe same method as used for 38d. Yield: 84.4%. ¹H NMR (500 MHz, CDCl₃) δ7.75-7.77 (d, 2H, J=7.5 Hz), 7.27-7.26 (d, 2

H, J=7.5 Hz), 7.23 (s, 1H), 5.62 (br, 1H), 4.87 (br, 1H), 4.30 (br, 2H),3.86 (s, 3H), 3.78 (t, J=10.0 Hz, 1H), 3.48-3.4 (m, 1H), 3.25 (s, 3H),1.42 (s, 9H). MS (ESI) m/z 402.1 (M+Na)⁺, 378.0 (M−H)⁻.

tert-Butyl 4-(4-(3,4,5-trimethoxybenzoyl)thiazol-2-yl)benzylcarbamate(68a). A mixture of 67a (2.5 mmol), CBrCl₃ (3.2 mmol) and DBU (5.0 mmol)in CH₂Cl₂ (20 mL) was stirred overnight. The reaction mixture wasabsorbed on silica gel and purified by column chromatography to yield anintermediate thiazole Weinreb amide. To a solution of(3,4,5-trimethoxyphenyl)magnesium bromide (0.5 M, 5.5 mL) in THF wasadded a solution of the intermediate thiazole Weinreb amide (1.83 mmol)in 10 mL THF under 0° C. and stirred for 30 min. The reaction mixturewas quenched with satd. NH₄Cl, extracted with ethyl ether, dried withMgSO₄. The solvent was removed under reduced pressure to yield a crudeproduct, which was purified by column chromatography to obtain purecompound as a light yellow solid (32.3%). ¹H NMR (300M, CDCl₃) δ 8.27(s, 1H), 7.98 (d, 2H, J=8.1 Hz), 7.78 (s, 2 H), 7.39 (d, 2H, J=8.1 Hz),7.27-7.26 (d, 2H, J=7.5 Hz), 7.23 (s, 1H), 4.93 (br, 1H), 4.37 (br, d,1H), 3.96 (s, 3H), 3.95 (s, 6H), 1.47 (s, 9H); MS (ESI) m/z 507.1(M+Na)⁺.

(2-(4-(Aminomethyl)phenyl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanonehydrochloride (2r or 2r-HCl). At 0° C., to a solution of 68a (200 mg) in10 ml, CH₂Cl₂ was added a solution of HCl in 1,4-dioxane (4 N, 2 mL) andstirred at RT for 4 h. The precipitate (2r) was filtered and washed withdiethyl ether. Yield: 81.3%. ¹H NMR (500 MHz, DMSO-d₆) δ 8.68 (s, 1H),8.38 (br, 3H), 8.10 (d, 2H, J=8.4 Hz), 7.66 (d, 2H, J=8.4 Hz), 7.62 (s,2H), 4.11 (s, 2H), 3.87 (s, 6H), 3.80 (s, 3H). MS (ESI) m/z 385.1(M+H)⁺.

(2-(4-((Dimethylamino)methyl)phenyl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanonehydrochloride (2u or 2u-HCl) [FIG. 5]

tert-Butylmethyl(4-(4-(3,4,5-trimethoxybenzoyl)thiazol-2-yl)benzyl)carbamate(71a). At 0° C., to a solution of compound 68a (100 mg, 0.2 mmol) in 5mL DMF was added sodium hydride (10 mg, 0.2 mmol), then iodomethane (77mg, 0.4 mmol) was added to the reaction mixture and stirred at RTovernight. The mixture was quenched with a sat. NaHCO₃ solution,extracted with ethyl acetate and dried with MgSO₄. The solvent wasremoved under reduced pressure to yield a crude product, which waspurified by column chromatography to obtain pure compound 71a. Yield:61.3%. ¹H NMR (500 MHz, DMSO-d₆) δ 8.30 (s, 1H), 8.02 (d, 2H, J=8.0 Hz),7.82 (s, 2H), 7.36 (br, 2H), 4.50 (s, 2H), 4.00 (s, 3H), 3.98 (s, 6H),2.90 (d, br, 3H), 1.50 (s, 9H). MS (ESI) m/z 521.2 (M+Na)⁺, 496.9(M−H)⁻.

(2-(4-((Methylamino)methyl)phenypthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanonehydrochloride (2s or 2s-HCl). At 0° C., to a solution of 71a (60 mg) in5 mL CH₂Cl₂ was added a solution of HCl in 1,4-dioxane (4 N, 2 mL) andstirred at RT for overnight. The precipitate (2s-HCl) was filtered andwashed with diethyl ether. Yield: 81.3%. ¹H NMR (500 MHz, CDCl₃) δ 10.0(s, 1H), 8.29 (s, 1H), 8.05 (d, 2H, J=6.0 Hz), 7.74 (s, 2H), 7.72 (d,2H, J=6.0 Hz), 4.15 (s, 2H), 3.99 (s, 3H), 3.96 (s, 6H), 2.61 (s, 3H).MS (ESI) m/z 399.1 (M+H)⁺.

(2-(4-((Dimethylamino)methyl)phenyl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanonehydrochloride (2u or 2u-HCl). To a solution of 2r (53 mg, 0.14 mmol) in5 mL CH₂Cl₂ was added formaldehyde solution (37% in H₂O, 340 mg, 4.2mmol), and sodium cyanoborohydride (34 mg, 0.55 mmol), the reactionmixture was absorbed on silica gel and free base was purified afterflash column (41 mg, 70.9%). At 0° C., to a solution of free base (41mg) in 5 mL CH₂Cl₂ was added a solution of HCl in 1,4-dioxane (4 N, 2mL) and stirred at RT for overnight. The precipitate (2u) was filteredand washed with diethyl ether. Yield: 71.3%. ¹H NMR (500 MHz, CDCl₃) δ13.0 (s, 1H), 8.34 (s, 1H), 8.13 (d, 2H, J=7.0 Hz), 7.82 (d, 2H, J=7.5Hz), 7.75 (s, 2H), 4.24 (s, 2H), 3.99 (s, 3H), 3.97 (s, 6H), 2.83 (s,6H). MS (ESI) m/z 413.1 (M+H)⁺.

2-(4-(4-(3,4,5-Trimethoxybenzoyl)thiazol-2-yl)phenyl)acetonitrile (2n)

2-(4-(4-(3,4,5-Trimethoxybenzoyl)thiazol-2-yl)phenyl)acetonitrile (2n)was prepared using the same method as used of compound 1h fromterephthalonitrile and cysteine. ¹H NMR (500 MHz, CDCl₃) δ 8.30 (s, 1H),8.04 (d, 2H), 7.76 (s, 2H), 7.46 (d, 2H), 3.97 (s, 3H), 3.95 (s, 6H),3.83 (s, 2H).

Synthesis of(2-(4-(Dimethylamino)phenyl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(2o)

(2-(4-(Dimethylamino)phenypthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(20) was prepared using the same method as used of compound 1h from4-(dimethylamino)benzonitrile and cysteine. ¹H NMR (300 MHz, CDCl₃) δ8.12 (s, 1H), 7.88 (d, 2H), 7.80 (s, 2H), 6.73 (d, 2H), 3.96 (s, 3H),3.95 (s, 6H), 3.05 (s, 6H); MS (ESI) m/z 421.1 (M+Na)⁺.

Indolyl A Ring:

Synthesis of(2-(1H-indol-2-yOthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (62a)[FIG. 5]

1H-Indole-2-carbonitrile (60a). To a cooled solution ofindole-2-carboxylic acid (2.0 g, 12.4 mmol) in 60 mL of anhydrous Et₂Owas added 1.9 mL of SOCl₂ (26 mmol). After stirring for 40 min at RT,the ether was removed under reduced pressure at a temperature notexceeding 35° C. The obtained acyl chloride was dissolved in 40 mL ofanhydrous Et₂O and the resulting solution was added immediately to astirred solution of liquid ammonia in 80 ml of Et₂O. The reactionmixture was stirred at RT for 24 h. The solvent was then evaporatedunder reduced pressure, and the white indole-2-carboxamide wascrystallized from 50% aq EtOH and dried in air, after which it wasdissolved in POCl₃ and heated under reflux for 5 min. The cooledsolution was poured onto crushed ice and aq NH₄OH was added to maintaina basic pH. The aqueous mixture was extracted with Et₂O, the extractswere dried over Na₂SO₄ and evaporated. The brown indole-2-carbonitrile60a (63.3% overall yield from indole-2-carboxylic acid) was obtained. ¹HNMR (500 MHz, CDCl₃) δ 8.56 (br, s, 1H), 7.68 (d, 1H, J=8.0 Hz),7.43-7.34 (m, 2H), 7.24-7.21 (m, 2H). MS (ESI) m/z 144.0 (M+H)⁺, 140.8(M−H)⁻.

(R)-2-(1H-indol-2-yl)-N-methoxy-N-methyl-4,5-dihydrothiazole-4-carboxamide(61a) was synthesized using the same method as used of 38d. 67.1% yield.¹H NMR (300 MHz, CDCl₃) δ 9.06 (s, br, 1H), 7.64 (d, 2H, J=8.1 Hz),7.36-7.24 (m, 2H), 7.12 (dt, 1H, J=8.1 Hz, 1.2 Hz), 6.95 (d, 1H, J=1.8Hz), 5.60 (t, br, 1H, J=8.7 Hz), 3.86 (s, 3H), 3.78 (t, 1H, J=10.2 Hz),3.58 (dd, 1H, J=9.0 Hz, 10.2 Hz), 3.30 (s, 3H). MS (ESI) m/z 312.1(M+Na)⁺, 287.9 (M(2-(1H-indol-2-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (62a)was synthesized from 61a using the same method as used for 35a. 45.8%yield. ¹H NMR (500 MHz, DMSO-d₆) δ 9.26 (s, 1H), 8.11 (s, 1H), 7.66 (d,1H, J=8.0 Hz), 7.46 (s, 2H), 7.42 (d, 1H, J=8.0 Hz), 7.29 (t, 1H, J=7.5Hz), 7.16 (t, 1H, J=7.5 Hz), 7.10 (s, 1H), 3.97 (s, 3H), 3.93 (s, 6H).MS (ESI) m/z 417.1 (M+Na)⁺, 392.9 (M−H)⁻.

Synthesis of(2-(1H-indol-5-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (66a)[FIG. 5]

(R)-2-(1-(Phenylsulfonyl)-1H-indol-5-yl)-4,5-dihydrothiazole-4-carboxylicacid (64a). (R)-2-(1H-indol-5-yl)-4,5-dihydrothiazole-4-carboxylic acid63a was synthesized using the same method as used for 42a from1H-indole-5-carbonitrile and used without further purification. To avigorously stirring solution of 63a (1 mmol) and tetrabutylammoniumhydrogen sulfate (0.15 mmol) in toluene (10 mL) at 0° C. was added 50%aqueous sodium hydroxide (10 mL) and sulfonyl chloride (2 mmol). Theresultant solution was stirred at RT for 6 h. Then 1 N HCl was added toacidify the mixture to pH=2 and extracted with CH₂Cl₂, the organic layerwas separated and dried (MgSO₄); then evaporated to dryness to yield64a, which were used in subsequent steps without further purification.

(R)—N-methoxy-N-methyl-2-(1-(phenylsulfonyl)-1H-indol-5-yl)-4,5-dihydrothiazole-4-carboxamide(65a) was prepared from 64a with the same method as used for 38d. 57.1%yield. ¹H NMR (500 MHz, CDCl₃) δ 7.92 (m, 2H), 7.77 (m, 3H), 7.51 (d,1H, J=3.0 Hz), 7.46 (t, 1H), 7.35 (t, 1H), 6.61 (d, 1H), 5.58 (br, t,1H) 3.82 (s, 3H), 3.73 (t, 1H), 3.43 (m, 1H), 3.21 (s, 3H). MS (ESI) m/z452.1 (M+Na)⁺.

(2-(1H-indol-5-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (66a).To a solution of n-BuLi (1.6 M, 1.7 mL) in 8 mL THF was added a solutionof 3,4,5-trimethoxybromobenzene (2.47 mmol) in 3 mL THF under −78° C.The mixture was allowed to stir for 2 h and a solution of Weinreb amide65a (1.24 mmol) in 3 mL THF was charged. The temperature was allowed toincrease at RT and stirred overnight. The reaction mixture was quenchedwith satd. NH₄Cl, extracted with ethyl ether, dried with MgSO₄. Thesolvent was removed under reduced pressure to yield a crude product,which was refluxed in 1 N NaOH in 5 mL ethanol solution to obtain thedeprotected compound 66a and purified by column chromatography to obtainpure compound as a light yellow solid (36.3%). ¹H NMR (300M, CDCl₃) δ8.36 (br, s, 1H), 8.31 (s, 1H), 8.21 (s, 1H), 7.92, 7.89 (dd, 1H, J=1.8,2.7 Hz), 7.46 (d, 1H) 7.62 (s, 2H, J=8.7 Hz), 7.29 (t, 1H, J=2.7 Hz),6.64 (br, 1H), 3.97 (s, 6H), 3.97 (s, 3H); MS (ESI) m/z 417.1 (M+Na)⁺,392.9 (M−H)⁻.

Synthesis of (2-(1H-Indol-2-yl)thiazol-4-yl)(1H-indol-2-yl)methanone (8)

(2-(1H-Indol-2-yl)thiazol-4-yl)(1H-indol-2-yl)methanone (8) was preparedusing the similar method as used of compound 1h from2-(1H-indol-2-yl)-4,5-dihydrothiazole-4-carboxylic acid and cysteine. ¹HNMR (500 MHz, CDCl₃) δ 9.39 (s, 1H), 8.54 (s, 1H), 8.46 (s, 1H), 8.06(s, 1H), 8.03 (dd, 1H), 7.66 (d, 1H), 7.51 (d, 1H), 7.41 (d, 1H), 7.33(t, 1H), 7.29 (d, 1H), 7.15 (t, 1H), 7.09 (d, 1H), 6.72 (s, 1H). MS(ESI) m/z 366.1 (M+Na)⁺, 341.9 (M−H)⁻.

Synthesis of (2-(1H-indol-2-yl)thiazol-4-yl)(1H-indol-5-yl)methanone(21)

(2-(1H-indol-2-yl)thiazol-4-yl)(1H-indol-5-yl)methanone (21) wasprepared using the similar method as used of compound 1h from2-(1H-indol-2-yl)-4,5-dihydrothiazole-4-carboxylic acid and cysteine. ¹HNMR (500 MHz, CDCl₃) δ 9.60 (s, 1H), 9.26 (s, 1H), 8.31 (s, 1H), 8.03(s, 1H), 7.83 (dd, 1H), 7.69 (d, 1H), 7.53-7.49 (m, 2H), 7.41 (t, 1H),7.33 (t, 1H), 7.21-7.18 (m, 2H), 7.13 (s, 1H). MS (ESI) m/z 366.1(M+Na)⁺, 341.9 (M−H)⁻.

Example 4 Synthesis of Compounds of this Invention Having a NitrogenLinker(X═NH)

To improve bioavailability, an NH linker was introduced between A phenyland B thiazole rings. This new series of compounds was synthesized asshown in FIG. 6. Reaction of 3-bromo-2-oxopropanoic acid ethyl ester andarylthiourea in ethanol under 65° C. produced2-(arylamino)-thiazole-4-carboxylic acids 73a-c with high yields. Theseacids were converted to Weinreb amides 74a-c, followed by reactions with3,4,5-trimethoxphenyllithium that yielded aniline linked free bases5a-c, which can be converted into HCl salts 5Ha-c.

Synthesis of(2-(Phenylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanonederivatives (5a-c) and their HCl salt [FIG. 6]

General procedure for the synthesis of 2-(arylamino)thiazole-4-carboxylic acids (37a-c). N-Aryl thiourea (0.01 mol) andethyl bromopyruvate (0.011 mol) were dissolved in 3 mL ethanol and heldat reflux for 2 h. The reaction was cooled, the crystalline ethyl2-(substituted phenylamino) thiazole-4-carboxylate were collected byfiltration and washed with ethanol. Refluxing the mixture of ethylesters with the NaOH-ethanol solution gave final compounds 73a-c whichwere used directly in the next steps.

N-Methoxy-N-methyl-2-(arylamino)thiazole-4-carboxamides (74a-c) weresynthesized using the same method as used for 38d (see Example 1, FIG.2)

N-Methoxy-N-methyl-2-(phenylamino)thiazole-4-carboxamide (74a). 90.2%yield. ¹H NMR (500 MHz, CDCl₃) δ 7.39 (s, 2H), 7.38 (br, 1H), 7.36-7.33(m, br, 4 H), 7.09 (t, br, 1H), 3.77 (s, 3H), 3.43 (s, 3H), 2.33 (s,3H). MS (ESI) m/z 286.0 (M+Na)⁺.

N-Methoxy-N-methyl-2-(p-tolylamino)thiazole-4-carboxamide (74b). 93.3%yield. ¹H NMR (500 MHz, CDCl₃) δ 7.35 (s, 1H), 7.31 (br, 1H), 7.22 (d,2H), 7.16 (d, 2H), 3.76 (s, 3H), 3.42 (s, 3H), 2.33 (s, 3H). MS (ESI)m/z 278.0 (M+H)⁺.

2-(4-Fluorophenylamino)-N-methoxy-N-methylthiazole-4-carboxamide (74c).89.7% yield. ¹H NMR (500 MHz, CDCl₃) δ 7.36 (s, 1H), 7.36-7.31 (m, 2H),7.07-7.04 (m, 6H), 3.76 (s, 3H), 3.42 (s, 3H). MS (ESI) m/z 282.0(M+Na)⁺, 280.8 (M−H)⁻.

General procedure for the synthesis of(2-(arylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanones (5a-c). At−78° C., to a solution of 5-bromo-1,2,3-trimethoxybenzene (1.235 g, 5.0mmol) in 30 mL THF was charged n-BuLi in hexane (2.5 N, 2.4 mL, 6 mmol)under Ar₂ protection and stirred for 10 min. Weinreb amide 74a-c (1mmol) in 10 mL THF was added to the lithium reagent and allowed to stirat RT for 2 hs. The reaction mixture was quenched with satd. NH₄Cl,extracted with ethyl ether, dried with MgSO₄. The solvent was removedunder reduced pressure to yield a crude product, which was purified bycolumn chromatography to obtain pure compound (5a-c).

(2-(Phenylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (5a).33.3% yield. ¹H NMR (500 MHz, DMSO-d₆) δ 10.4 (s, 1H), 7.85 (s, 1H),7.68 (d, 2H, J=8.0 Hz), 7.31 (t, 2H, J=8.0 Hz), 6.98 (t, 1H, J=8.0 Hz),3.83 (s, 6H), 3.78 (s, 3H). MS (ESI) m/z 393.1 (M+H)⁺, 368.9 (M

(2-(p-Tolylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (5b).40.6% yield. ¹H NMR (500 MHz, CDCl₃) δ 7.48 (s, 1H), 7.47 (s, 2H), 7.30(br, 1H), 7.27 (d, 2H, J=8.5 Hz), 7.17 (d, 2H, J=8.5 Hz), 3.93 (s, 3H).3.90 (s, 6H), 2.34 (s, 3H). MS (ESI) m/z 385.1 (M+H)⁺, 382.9 (M

(2-(p-Fluorophenylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(5c). 39.6% yield. ¹H NMR (500 MHz, CDCl₃) δ 7.52 (br, 1H), 7.49 (s,1H), 7.45 (s, 2H), 7.40-7.37 (q, 2H, J=4.5 Hz), 7.08-7.04 (t, 2H, J=8.0Hz), 3.93 (s, 3H), 3.89 (s, 6H). MS (ESI) m/z 389.3 (M+H)⁺, 386.9(M−H)⁻.

General procedure for the synthesis of hydrochloride salts (5Ha-c). At0° C., to a solution of compound 5a-c (0.1 mmol) in 5 mL CH₂Cl₂ wasadded a solution of HCl in 1,4-dioxane (4 N, 2 mL) and stirred at RT forovernight. The precipitates 5Ha-c were collected and washed with diethylether.

(2-(Phenylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanonehydrochloride salt (5Ha). 91.6% yield. ¹H NMR (500 MHz, DMSO-d₆) δ 12.9(br, 1H), 7.49-7.46 (m, 2H), 7.42-7.40 (m, 2H), 7.37-7.34 (m, br, 2H),7.11 (s, 2H), 3.94 (s, 3H), 3.92 (s, 6H). MS (ESI) m/z 389.1 (M+H)⁺.

(2-(p-Tolylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanonehydrochloride salt (5Hb). 39.6% yield. ¹H NMR (500 MHz, CDCl₃) δ7.30-7.25 (m, br, 5 H), 7.12 (s, 2H), 3.94 (s, 3H), 3.92 (s, 6H), 2.38(s, 3H). MS (ESI) m/z 389.1 (M+H)⁺.

(2-(p-Fluorophenylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanonehydrochloride salt (5Hc). 89.3% yield. ¹H NMR (500 MHz, CDCl₃) δ 10.55(s, 1H), 7.85 (s, 1H), 7.72-7.69 (q, 2H, J=4.5 Hz), 7.50 (s, 2H),7.18-7.15 (t, 2H, J=8.5 Hz), 4.30 (br, 1 H), 3.82 (s, 6H), 3.78 (s, 3H).MS (ESI) m/z 389.3 (M+H)⁺.

Example 5 Synthesis of Selected Aryl-Benzoyl-Imidazole Compounds

Preparation of 2-aryl-4,5-dihydro-1H-imidazoles 14b, 14c, 14x (FIG. 7)

To a solution of appropriate benzaldehyde 8(b, c, x) (60 mmol) in t-BuOH(300 mL) was added ethylenediamine (66 mmol) and stirred for 30 min atRT. Potassium carbonate (75 mmol) and iodine (180 mmol) were added tothe reaction mixture sequentially followed by stirring at 70° C. for 3h. Sodium sulfite (Na₂SO₃) was added and the mixture was extracted bychloroform. The organic layer was dried over magnesium sulfate andconcentrated. The residue was purified by flash column chromatography(chloroform:methanol 20:1) to give a white solid. Yield: 50-60%.

Preparation of 2-aryl-1H-imidazoles (9a-j, p, x; FIGS. 7 and 8)

Method A (essential for only 9b, 9x FIG. 7): To a solution of2-aryl-4,5-dihydro-1H-imidazole 14b, x (35 mmol) in DMSO (100 mL) wasadded potassium carbonate (38.5 mmol) and diacetoxyiodobenzene (38.5mmol). The reaction mixture was stirred overnight in darkness. Water wasadded followed by extraction with dichloromethane. The organic layer wasdried over magnesium sulfate and concentrated. The residue was subjectedto flash column chromatography (hexane:ethyl acetate 3:2) to give awhite solid. Yield: 30%-50%.

Method B (essential for only 9c; FIG. 7): To a solution of2-aryl-4,5-dihydro-1H-imidazole 14c (50 mmol) in DMF (70 mL) was addedDBU (55 mmol) and CBrCl₃ (55 mmol). The reaction mixture was stirredovernight and a saturated NaHCO₃ (aqueous) solution was added followedby extraction with dichloromethane. The organic layer was dried overmagnesium sulfate and concentrated. The residue was subjected to flashcolumn chromatography (chloroform:methanol 50:1) to yield a white solid.Yield: 7%.

Method C (essential for 9a, 9d-j, 9p; FIG. 8): To a solution ofappropriate benzaldehyde (8a, 8d-j, 8p) (100 mmol) in ethanol (350 mL)at 0° C. was added a solution of 40% oxalaldehyde in water (12.8 mL, 110mmol) and a solution of 29% ammonium hydroxide in water (1000 mmol, 140mL). After stirring for 2-3 days at RT, the reaction mixture wasconcentrated and the residue was subjected to flash columnchromatography with dichloromethane as eluent to yield the titledcompound as a yellow powder. Yield: 20%-40%.

Preparation of 2-aryl-1-(phenylsulfonyl)-1H-imidazoles (10a-j, p, x;FIGS. 7 and 8)

To a solution of 2-aryl-1H-imidazole 9a-j, p, x (20 mmol) in anhydrousTHF (200 mL) at 0° C. was added sodium hydride (60% dispersion inmineral oil, 1.2 g, 30 mmol) and stirred for 30 min. Benzenesulfonylchloride (2.82 mL, 22 mmol) was added and the reaction mixture wasstirred overnight. After dilution by 100 mL of saturated NaHCO₃ solution(aqueous), the reaction mixture was extracted by ethyl acetate (500 mL).The organic layer was dried over magnesium sulfate and concentrated. Theresidue was purified by flash column chromatography (hexane:ethylacetate 2:1) to give a pale solid. Yield: 50%-70%.

Preparation of aryl(2-aryl-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanones (11aa-ai, ba, ca,cb, da, db, ea, eb, fa, fb, ga, gb, ha, hb, ia, ib, ja, jb, pa; FIGS. 7and 8).

To a solution of 2-aryl-1-(phenylsulfonyl)-1H-imidazole (6.0 mmol)10a-j, p, x in anhydrous THF (30 mL) at −78° C. was added 1.7Mtert-butyllithium in pentane (5.3 mL, 9.0 mmol) and stirred for 10 min.Appropriate substituted benzoyl chloride (7.2 mmol) was added at −78° C.and stirred for overnight. The reaction mixture was diluted with 100 mLof saturated NaHCO₃ solution (aqueous) and extracted by ethyl acetate(200 mL). The organic layer was dried over magnesium sulfate andconcentrated. The residue was purified by flash column chromatography(hexane:ethyl acetate 4:1) to give a white solid. Yield: 15%-40%.General procedure for the preparation of aryl(2-aryl-1H-imidazol-4-yl)methanones (12aa-ai, ba, ca, cb, da, db, ea,eb, fa, fb, ga, gb, ha, hb, ia, ib, ja, jb, pa; FIGS. 7 and 8).

To a solution of aryl(2-aryl-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanones (2.0 mmol)11aa-ai, ba, ca, cb, da, db, ea, eb, fa, fb, ga, gb, ha, hb, ia, ib, ja,jb, pa in THF (20.0 mL) was added 1.0M tetrabutyl ammonium fluoride (4.0mmol) and stirred overnight. The reaction mixture was diluted by 50 mLof saturated NaHCO₃ solution (aqueous) and extracted by ethyl acetate(100 mL). The organic layer was dried over magnesium sulfate andconcentrated. The residue was purified by flash column chromatography(hexane:ethyl acetate 3:1) or recrystallized from water and methanol togive a white solid. Yield: 80-95%.

Preparation of (2-(4-hydroxyphenyl)-1H-imidazol-4-yl) (aryl)methanones(12ka, 12 kb; FIG. 8).

To a solution of(2-(4-(benzyloxy)phenyl)-1H-imidazol-4-yl)(aryl)methanone 12ja or 12jb,(1 mmol) in AcOH (20 mL) was added concentrated HCl (2 mL) and refluxedovernight. After removing the solvent, the residue was recrystallizedfrom dichloromethane to give the titled compound as a yellow solid.Yield: 70-85%.

Preparation of (2-aryl-1H-imidazol-4-yl)(3,4,5-trihydroxyphenyl)methanones 13ea, 13fa, 13ha (FIG. 8).

To a solution of aryl (2-aryl-1H-imidazol-4-yl)methanone 12ea, 12fa or12ha (0.5 mmol) in CH₂Cl₂ (6.0 mL) was added 1.0 M of BBr₃ (2 mmol) inCH₂Cl₂ and stirred for 1 h at RT. Water was added to destroy excessBBr₃. The precipitated solid was filtered and recrystallized from MeOHto afford a yellow solid. Yield: 60-80%.

Preparation of aryl (2-aryl-1H-imidazol-4-v1)methanone-HCl salt (12db-HCl)

To a solution of 12 db (0.5 mmol) in methanol (20 mL) was added 2Msolution of hydrogen chloride (5 mmol) in ethyl ether and stirredovernight at RT. The reaction mixture was concentrated and the residuewas washed by CH₂Cl₂ to yield the titled compound. Yield: 95%.

Preparation of aryl (2-phenyl-1H-imidazol-1-yl)methanone (12aba, 12aaa;FIG. 9)

To a solution of 2-phenyl-1H-imidazole 9a (10 mmol) in THF (20 mL) wasadded NaH (15 mmol) and substituted benzoyl chloride (12 mmol) at 0° C.The reaction mixture was stirred overnight and diluted by saturatedNaHCO₃ solution followed by extraction with ethyl acetate. The organiclayer was dried over magnesium sulfate and concentrated. The residue waspurified by flash column chromatography (chloroform) to give a whitesolid. Yield: 12-16%.

Preparation of 1-substituted-(2-phenyl-1H-imidazol-1-yl)-aryl-methanone(12dc, 12fc, 12daa, 12 dab, 12 cba, 11gaa, 12la; FIGS. 10-11).

The synthesis of 12dc, 12fc and 12daa, 12dab and 12cba is summarized inFIG. 10. Compounds 12da, 12cb and 12fa were synthesized according to thesynthesis described above and in FIGS. 7 and 8. Treatment of 12da and12fa with aluminum chloride provided the para-demethylated 12dc, 12fcwith the 3,5-dimethoxy being intact. Compound 12daa was prepared bybenzylation of the N-1 position of 12da. While methylation of the N-1position of 12da and 12cb afforded compounds 12dab and 12cba,respectively.

Synthesis of 12dc, 12fc, 12daa, 12dab, 12cba: Method D. (for 12dc and12fc) [FIG. 10]:

R₁═CH₃ (12dc) R₁═Cl (12fc)

To a solution of 12da and 12fa (200 mg) in THF (20 mL) was addedaluminum chloride (10 equiv). The reaction mixture was stirredovernight. Water was added followed by extraction with ethyl acetate.The organic layer was dried over magnesium sulfate and concentrated. Theresidue was subjected to flash column chromatography (hexane:ethylacetate 1:1) to give a white-yellowish solid. Yield: 60%-80%.

Synthesis of 12daa, 12dab, 12cba, Method E: [FIG. 10]

R₁=Me; R₂=Bn; R₃=3,4,5-(OMe)₃(12daa)R₁=Me; R₂═CH₃; R₃=3,4,5-(OMe)₃(12dab)R₁═OMe; R₂═CH₃; R₃═F (12cba)

To a solution of 12da and 12cb (100 mg) in THF (10 mL) in an ice-bathwas added sodium hydride (1.2 equiv) followed by the addition of methyliodide (for 12dab, 12cba) or benzyl bromide (for 12daa) (2 equiv). Theresulted reaction mixture was stirred for 5 h under reflux condition.After dilution by 50 mL of saturated NaHCO₃ solution (aqueous), thereaction mixture was extracted by ethyl acetate (100 mL). The organiclayer was dried over magnesium sulfate and concentrated. The residue waspurified by flash column chromatography (hexane:ethyl acetate 2:1) togive a white solid. Yield: 50%-98%.

Synthesis of 11gaa and 12la (FIG. 11)

R₁═N(Me)₂; R₂=(4-OMe)PhSO₂ (11gaa)

R₁═Br; R₂═H (12la)

The substituted benzaldehyde compounds 8(l, g) were converted tocompounds 9(1, g) in the presence of ammonium hydroxide and glyoxal toconstruct the imidazole scaffold. The imidazole rings of compounds 9(l,g) were protected by an appropriate phenyls'ulfonyl group followed bycoupling with 3,4,5-trimethoxybenzoyl chloride to achieve compound11(la,gaa). Treatment of 11la with tert-butylammoniumfluoride to removethe protecting group afforded 12la.

Structural characterization of(1-Benzyl-2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12daa) (FIG. 11)

Yield: 92.8%; mp 135-137° C. ¹H NMR (CDCl₃, 500 MHz) δ 7.81 (s, 1H),7.80 (d, J=6.5 Hz, 2H), 7.58 (d, J=8.0 Hz, 2H), 7.41-7.45 (m, 3H),7.31-7.33 (m, 2H), 7.20 (d, J=7.0 Hz, 2H), 5.33 (s, 2H), 3.99 (s, 3H),3.98 (s, 6H), 2.47 (s, 3H). MS (ESI) calcd for C₂₇H₂₆N₂O₄ 442.2. Found443.1 [M+Na]⁺. HPLC1: t_(R) 4.28 min, purity>99%.

Structural characterization of(2-(4-(dimethylamino)phenyl)-1-((4-methoxyphenyl)sulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12gba)

Yield: 34.1%; mp 147-149° C. ¹H NMR (CDCl₃, 500 MHz) δ 8.07 (q, J=8.5Hz, 5.5 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.41 (d, J=8.5 Hz, 2H), 7.39(s, 1H), 7.23 (t, J=8.5 Hz, 2H), 6.91 (d, J=9.0 Hz, 2H), 6.68 (d, J=9.0Hz, 2H), 3.89 (s, 3H), 3.08 (s, 3H). MS (ESI) calcd for C₂₅H₂₂FN₃O₄S479.1. Found 502.1 [M+Na]⁺. HPLC2: t_(R) 18.6 min, purity 96.9%.

Synthesis of(2-(4-bromophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12la) (FIG. 11)

Synthesis of 9l, 9g: To a solution of appropriate benzaldehyde (8l, and8g, 100 mmol) in ethanol (400 mL) at 0° C. was added a solution of 40%oxalaldehyde (glyoxal) in water (1.1 equiv) and a solution of 29%ammonium hydroxide in water (10 equiv). After stirring for 2-3 days atRT, the reaction mixture was concentrated and the residue was subjectedto flash column chromatography with dichloromethane as eluent to yieldthe titled compound as a yellow powder. Yield: 10%-30%.

Synthesis of 10la, 10gb: To a solution of imidazoles (9l, 9g) (10 mmol)in anhydrous THF (200 mL) at 0° C. was added sodium hydride (60%dispersion in mineral oil, 1.2 equiv) and stirred for 20 min.4-Methoxybenzenesulfonyl chloride (for 10gb) or benzenesulfonyl chloride(for others)(1.2 equiv) was added and the reaction mixture was stirredovernight. After dilution by 200 mL of saturated NaHCO₃ solution(aqueous), the reaction mixture was extracted by ethyl acetate (600 mL).The organic layer was dried over magnesium sulfate and concentrated. Theresidue was purified by flash column chromatography (hexane:ethylacetate 2:1) to give a pale solid. Yield: 40%-95%. Synthesis of 11la,11gaa: To a solution of 2-aryl-1-(phenylsulfonyl)-1H-imidazole (10la,10gb) (5.0 mmol) in anhydrous THF (30 mL) at −78° C. was added 1.7 Mtert-butyllithium in pentane (1.2 equiv) and stirred for 10 min.3,4,5-Trimethoxybenzoyl chloride (1.2 equiv) was added at −78° C. andstirred overnight. The reaction mixture was diluted with 100 mL ofsaturated NaHCO₃ solution (aqueous) and extracted by ethyl acetate (300mL). The organic layer was dried over magnesium sulfate andconcentrated. The residue was purified by flash column chromatography(hexane:ethyl acetate 3:1) to give a white solid. Yield: 5%-45%.Synthesis of 12la: To a solution of aryl(2-aryl-1-(phenylsulfonyl)-1H-imidazol-4-yl) methanone (11la), 2.0 mmol)in THF (25.0 mL) was added 1.0 M tetrabutyl ammonium fluoride (2 equiv)and stirred overnight. The reaction mixture was diluted by 60 mL ofsaturated NaHCO₃ solution (aqueous) and extracted by ethyl acetate (150mL). The organic layer was dried over magnesium sulfate andconcentrated. The residue was purified by flash column chromatography(hexane:ethyl acetate 4:1) or recrystallized from water and methanol togive a white solid. Yield: 80-98%. Synthesis of(4-Fluorophenyl)(2-(4-methoxyphenyl)-1H-imidazol-4-Amethanone (12cb)(FIG. 7).

To a solution of(4-fluorophenyl)(2-(4-methoxyphenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone(11cb, 872 mg, 2.0 mmol) in THF (20.0 mL) was added 1.0M tetrabutylammonium fluoride (4.0 mL, 4.0 mmol) and stirred overnight. The reactionmixture was diluted by 50 mL of saturated NaHCO₃ solution (aqueous) andextracted by ethyl acetate (100 mL). The organic layer was dried overmagnesium sulfate and concentrated. The residue was recrystallized fromwater and methanol to give a white solid. Yield: 90%; mp 245-247° C.

Synthesis of(2-(p-Tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12da)(FIG. 8).

To a solution of(1-(phenylsulfonyl)-2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11da, 492 mg, 1.0 mmol) in THF (15.0 mL) was added 1.0 M tetrabutylammonium fluoride (2.0 mL, 2.0 mmol) and stirred overnight. The reactionmixture was diluted by 30 mL of saturated NaHCO₃ solution (aqueous) andextracted by ethyl acetate (80 mL). The organic layer was dried overmagnesium sulfate and concentrated. The residue was recrystallized fromwater and methanol to give a white solid. Yield: 88.5%.

Synthesis of(2-(4-Chlorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12fa) (FIGS. 8 and 14).

2-(4-Chlorophenyl)-1H-imidazole (9f): To a solution of4-chlorobenzaldehyde (81) (100 mmol) in ethanol (350 mL) at 0° C. wasadded a solution of 40% oxalaldehyde in water (12.8 mL, 110 mmol) and asolution of 29% ammonium hydroxide in water (1000 mmol, 140 mL). Afterstirring for 2-3 days at RT, the reaction mixture was concentrated andthe residue was subjected to flash column chromatography withdichloromethane as eluent to yield the titled compound as a yellowpowder. Yield: 19.8%. NMR (500 MHz, DMSO-d₆) δ 13.60 (br, 1H), 7.94 (d,J=8.5 Hz, 2H), 7.51 (d, J=8.0 Hz, 2H), 7.27 (s, 1H), 7.03 (s, 1H). MS(ESI): calculated for C₉H₇ClN₂, 178.0. Found 178.9 [M+H]⁺.

2-(4-Chlorophenyl)-1-(phenylsulfonyl)-1H-imidazole (101): To a solutionof 2-(4-chlorophenyl)-1H-imidazole (9f) (20 mmol) in anhydrous THF (200mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil,1.2 g, 30 mmol) and stirred for 30 min. Benzenesulfonyl chloride (2.82mL, 22 mmol) was added and the reaction mixture was stirred overnight.After dilution by 100 mL of saturated NaHCO₃ solution (aqueous), thereaction mixture was extracted by ethyl acetate (500 mL). The organiclayer was dried over magnesium sulfate and concentrated. The residue waspurified by flash column chromatography (hexane:ethyl acetate 2:1) togive a pale solid. Yield: 54.9%. ¹H NMR (500 MHz, CDCl₃) δ 7.65 (d,J=2.0 Hz, 1H), 7.58 (t, J=7.5 Hz, 1H), 7.43 (d, J=8.5 Hz, 2H), 7.38 (t,J=8.0 Hz, 2H), 7.34-7.36 (m, 4H), 7.12 (d, J=1.5 Hz, 1H). MS (ESI):calculated for C₁₅H₁₁ClN₂O₂S, 318.0. Found 341.0 [M+Na]⁺.

(2-(4-Chlorophenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11fa): To a solution of2-(4-chlorophenyl)-1-(phenylsulfonyl)-1H-imidazole (100 (6.0 mmol) inanhydrous THF (30 mL) at −78° C. was added 1.7 M tert-butyllithium inpentane (5.3 mL, 9.0 mmol) and stirred for 10 min.3,4,5-Trimethoxybenzoyl chloride (7.2 mmol) was added at −78° C. andstirred for overnight. The reaction mixture was diluted with 100 mL ofsaturated NaHCO₃ solution (aqueous) and extracted by ethyl acetate (200mL). The organic layer was dried over magnesium sulfate andconcentrated. The residue was purified by flash column chromatography(hexane:ethyl acetate 4:1) to give a white solid. Yield: 36.8%; ¹H NMR(500 MHz, CDCl₃) δ 8.05 (d, J=7.5 Hz, 2H), 7.77 (t, J=7.5 Hz, 1H), 7.62(t, J=8.0 Hz, 2H), 7.48 (s, 1H), 7.44 (d, J=9.0 Hz, 2H), 7.39 (d, J=8.5Hz, 2H), 7.37 (s, 2H). MS (ESI): calculated for C₂₅H₂₁ClN₂O₆S, 512.1.Found 513.1 [M+H]⁺.

(2-(4-Chlorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12fa): To a solution of(2-(4-chlorophenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11fa) (2.0 mmol) in THF (20.0 mL) was added 1.0 M tetrabutyl ammoniumfluoride (4.0 mmol) and stirred overnight. The reaction mixture wasdiluted by 50 mL of saturated NaHCO₃ solution (aqueous) and extracted byethyl acetate (100 mL). The organic layer was dried over magnesiumsulfate and concentrated. The residue was purified by flash columnchromatography (hexane:ethyl acetate 3:1) or recrystallized from waterand methanol to give a white solid. Yield: 80-95%. Yield: 36.9%; mp193-195° C. ¹H NMR (500 MHz, CDCl₃) δ 10.75 (br, 1H), 7.96 (d, J=8.5 Hz,2H), 7.83 (s, 1H), 7.47 (d, J=9.0 Hz, 2H), 7.23 (s, 2H), 3.97 (s, 3H),3.94 (s, 6H), 2.43 (s, 3H). MS (ESI): calculated for C₁₉H₁₇ClN₂O₄,372.1. Found 395.1 [M+Na]⁺, 370.9 [M−H]⁻. HPLC Gradient: Solvent A(water) and Solvent B (methanol): 0-15 min 40-100% B (linear gradient),15-25 min 100% B: t_(R) 16.36 min, purity>99%.

Synthesis of(2-(4-Chlorophenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone (12fb)(FIG. 8)

To a solution of(2-(4-chlorophenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(11fb, 440 mg, 1.0 mmol) in THF (12.0 mL) was added 1.0 M tetrabutylammonium fluoride (2.0 mL, 2.0 mmol) and stirred overnight. The reactionmixture was diluted by 20 mL of saturated NaHCO₃ solution (aqueous) andextracted by ethyl acetate (60 mL). The organic layer was dried overmagnesium sulfate and concentrated. The residue was recrystallized fromwater and methanol to give a white solid. Yield: 83.7%.

Physicochemical Characterization of Aryl-Benzoyl-Imidazole Compounds andIntermediates

Compound Physicochemical Cheracterization 2-phenyl-1H-imidazole (9a).Yield: 36.8%. ¹H NMR (500 MHz, DMSO-d₆) δ 12.52 (br, 1 H), 7.95 (d, J =7.0 Hz, 2 H), 7.44 (t, J = 7.5 Hz, 2 H), 7.34 (t, J = 7.0 Hz, 1H),7.25-7.27 m, 1 H), 7.04-7.07 m, 1 H). MS (ESI): calculated for C₉H₈N₂,144.1, found 167.1 [M + Na]⁺. 2-(4-fluorophenyl)-1H-imidazole (9b).Yield: 56.5%. ¹H NMR (300 MHz, DMSO-d₆) δ 12.46 (br, 1 H), 7.94-7.99 (m,2 H), 7.24-7.30 (m, 2 H), 7.00-7.03 (m, 2 H). MS (ESI): calculated forC₉H₇FN₂, 162.1, found 163 [M + H]⁺, 160.6 [M − H]⁻.2-(4-methoxyphenyl)-1H-imidazole (9c). Yield: 22.2%. ¹H NMR (500 MHz,CDCl₃) δ 7.80 (d, J = 10.0 Hz, 2 H), 7.15 (s, 2 H), 3.86 (s, 3 H). MS(ESI): calculated for C₁₀H₁₀N₂O, 174.1, found 175 [M + H]⁺, 172.8 [M −H]⁻. 2-(p-tolyl)-1H-imidazole (9d). Yield: 36.1%. ¹H NMR (500 MHz,CDCl₃) δ 7.64 (d, J = 7.5 Hz, 2 H), 7.16 (d, J = 7.5 Hz, 2 H), 7.12 (s,1 H), 7.02 (s, 1 H). MS (ESI): calculated for C₁₀H₁₀N₂, 158.1, found159.0 [M + H]⁺, 156.8 [M − H]⁻. 2-(3,4,5-trimethoxyphenyl)-1H-imidazole(9e). Yield: 26.0%. ¹H NMR (500 MHz, CDCl₃) δ 7.26 (s, 2 H), 7.08 (d, J= 1.5 Hz, 2 H), 3.86 (s, 3 H), 3.82 (s, 6 H). MS (ESI): calculated forC₁₂H₁₄N₂O₃, 234.1, found 234.9 [M + H]⁺. 2-(4-chlorophenyl)-1H-imidazole(9f). Yield: 19.8%. ¹H NMR (500 MHz, DMSO-d₆) δ 13.60 (br, 1 H), 7.94(d, J = 8.5 Hz, 2 H), 7.51 (d, J = 8.0 Hz, 2 H), 7.27 (s, 1 H), 7.03 (s,1 H). MS (ESI): calculated for C₉H₇ClN₂, 178.0, found 178.9 [M + H]⁺.4-(1H-imidazol-2-yl)-N,N-dimethylaniline (9g). Yield: 16.5%. ¹H NMR (300MHz, CDCl₃) δ 7.70 (dd, J = 7.0 Hz, 2.0 Hz, 2 H), 7.10 (s, 2 H), 6.75(dd, J = 9.0 Hz, 2.0 Hz, 2 H), 3.02 (s, 6 H). MS (ESI): calculated forC₁₁H₁₃N₃, 187.1, found 187.9 [M + H]⁺, 185.8 [M − H]⁻.2-(3,4-dimethoxyphenyl)-1H-imidazole (9h). Yield: 22.0%. ¹H NMR (500MHz, CDCl₃) δ 7.52 (d, J = 1.5 Hz, 1 H), 7.27-7.28 (m, 1 H), 7.14 (s, 2H), 6.88 (d, J = 8.0 Hz, 1 H), 3.91 (s, 3 H), 3.87 (s, 3 H). MS (ESI):calculated for C₁₁H₁₂N₂O₂, 204.1, found 205.1 [M + H]⁺, 202.8 [M − H]⁻.2-(2-(trifluoromethyl)phenyl)-1H-imidazole Yield: 25.5%. ¹H NMR (500MHz, DMSO-d₆) δ (9i). 12.31 (br, 1 H), 7.84 (d, J = 8.0 Hz, 1 H), 7.76(t, J = 8.0 Hz, 1 H), 7.65 (t, J = 7.5 Hz, 1 H), 7.16 (br, 2 H). MS(ESI): calculated for C₁₀H₇F₃N₂, 212.1, found 212.9 [M + H]⁺, 210.7 [M −H]⁻. 2-(4-(benzyloxy)phenyl)-1H-imidazole (9j). Yield: 12.1%. ¹H NMR(500 MHz, CDCl₃) δ 7.77 (d, J = 8.5 Hz, 2 H), 7.36-7.47 (m, 5 H),7.10-7.18 (m, 2 H), 7.06 (d, J = 9.0 Hz, 2 H), 5.13 (s, 2 H). MS (ESI):calculated for C₁₆H₁₄N₂O, 250.1, found 251.1 [M + H]⁺, 248.8 [M − H]⁻.2-(4-Bromophenyl)-1H-imidazole (9l). Yield: 19.5%. ¹H NMR (300 MHz,CDCl₃) δ 12.59 (s, 1 H), 7.87 (d, J = 8.1 Hz, 2 H), 7.64 (d, J = 8.1 Hz,1 H), 7.27 (s, 1 H), 7.04 (s, 1 H). MS (ESI) calcd for C₉H₇BrN₂ 222.0,found 222.8 [M + H]⁺. 2-(4-(Trifluoromethyl)phenyl)-1H-imidazole Yield:26.2%; ¹H NMR (500 MHz, CDCl₃) δ (9p). 8.03 (d, J = 8.0 Hz, 2 H), 7.66(d, J = 8.0 Hz, 2 H), 7.25 (s, 2 H). MS (ESI) calcd for C₁₀H₇F₃N₂ 212.1,found 213.1 [M + H]⁺. 2-(4-nitrophenyl)-1H-imidazole (9x). Yield: 53.7%.¹H NMR (500 MHz, DMSO-d₆) δ 12.97 (br, 1 H), 8.32 (d, J = 9.0 Hz, 2 H),8.17 (d, J = 9.0 Hz, 2 H), 7.42 (s, 1 H), 7.17 (s, 1H). MS (ESI):calculated for C₉H₇N₃O₂, 189.1, found 189.9 [M + H]⁺, 187.8 [M − H]⁻.2-phenyl-1-(phenylsulfonyl)-1H-imidazole Yield: 50.3%. ¹H NMR (500 MHz,CDCl₃) δ (10a). 7.64-7.67 (m, 1 H), 7.56 (t, J = 9.0 Hz, 1 H), 7.32-7.48(m, 9 H), 7.12-7.16 (m, 1 H). MS (ESI): calculated for C₁₅H₁₂N₂O₂S,284.1, found 307.1 [M + Na]⁺. 2-(4-fluorophenyl)-1-(phenylsulfonyl)-1H-Yield: 56.9%. ¹H NMR (500 MHz, CDCl₃) δ imidazole (10b). 7.66 (d, J =2.0 Hz, 1 H), 7.58 (t, J = 10.0 Hz, 1 H), 7.36-7.42 (m, 6 H), 7.12 (d, J= 2.0 Hz, 1 H), 7.06 (t, J = 10.0 Hz, 2 H). MS (ESI): calculated forC₁₅H₁₁FN₂O₂S, 302.1, found 300.8 [M − H]⁻.2-(4-methoxyphenyl)-1-(phenylsulfonyl)-1H- Yield: 40.9%. ¹H NMR (500MHz, CDCl₃) δ imidazole (10c). 7.62 (d, J = 5.0 Hz, 1 H), 7.56 (tt, J =15.0 Hz, 5.0 Hz, 1 H), 7.32-7.43 (m, 6 H), 7.10 (d, J = 5.0 Hz, 1 H),6.88 (dt, J = 16.0 Hz, 6.0 Hz, 2 H), 3.87 (s, 3 H). MS (ESI): calculatedfor C₁₆H₁₄N₂O₃S, 314.1, found 337.1 [M + Na]⁺, 312.9 [M − H]⁻.1-(phenylsulfonyl)-2-(p-tolyl)-1H-imidazole Yield: 46.6%. ¹H NMR (500MHz, CDCl₃) δ (10d). 7.63 (d, J = 1.0 Hz, 1 H), 7.55 (t, J = 8.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 2 H), 7.35 (t, J = 7.5 Hz, 2 H), 7.27-7.29 (m,2 H), 7.16 (d, J = 7.5 Hz, 2 H), 7.10 (s, 1 H), 2.41 (s, 3 H). MS (ESI):calculated for C₁₆H₁₄N₂O₂S, 298.1, found 321.1 [M + Na]⁺.1-(phenylsulfonyl)-2-(3,4,5- Yield: 55.7%. ¹H NMR (500 MHz, CDCl₃) δtrimethoxyphenyl)-1H-imidazole (10e). 7.68 (d, J = 1.5 Hz, 1 H), 7.55(t, J = 7.0 Hz, 1 H), 7.42 (d, J = 7.5 Hz, 2 H), 7.35 (t, J = 8.5 Hz, 2H), 7.11 (d, J = 1.5 Hz, 2 H), 6.60 (s, 1 H), 3.90 (s, 3 H), 3.79 (s, 6H). MS (ESI): calculated for C₁₈H₁₈N₂O₅S, 374.1, found 397.1 [M + Na]⁺.2-(4-chlorophenyl)-1-(phenylsulfonyl)-1H- Yield: 54.9%. ¹H NMR (500 MHz,CDCl₃) δ imidazole (10f). 7.65 (d, J = 2.0 Hz, 1 H), 7.58 (t, J = 7.5Hz, 1 H), 7.43 (d, J = 8.5 Hz, 2 H), 7.38 (t, J = 8.0 Hz, 2 H),7.34-7.36 (m, 4 H), 7.12 (d, J = 1.5 Hz, 1 H). MS (ESI): calculated forC₁₅H₁₁ClN₂O₂S, 318.0, found 341.0 [M + Na]⁺.N,N-dimethyl-4-(1-(phenylsulfonyl)-1H- Yield: 48.3%. ¹H NMR (300 MHz,CDCl₃) δ imidazol-2-yl) aniline (10g). 7.59 (d, J = 2.0 Hz, 1 H), 7.55(t, J = 8.0 Hz, 1 H), 7.45 (d, J = 7.5 Hz, 2 H), 7.28-7.38 (m, 4 H),7.07 (d, J = 2.0 Hz, 1 H), 6.68 (d, J = 8.5 Hz, 2 H), 3.04 (s, 3 H). MS(ESI): calculated for C₁₇H₁₇N₃O₂S, 327.10, found 350.0 [M + Na]⁺, 325.9[M − H]⁻. 4-(1-((4-Methoxyphenyl)sulfonyl)-1H- Yield: 61.5%. ¹NMR (500MHz, CDCl₃) δ imidazol-2-yl)-N,N-dimethylaniline (10gb). 7.58 (d, J =1.5 Hz, 1 H), 7.36 (t, J = 8.43 Hz, 4 H), 7.03-7.09 (m, 1 H), 6.80 (d, J= 9.0 Hz, 2 H), 6.69 (d, J = 8.8 Hz, 2 H), 3.84 (s, 3 H), 3.05 (s, 6 H).MS (ESI): calculated for C₁₇H₁₇N₃O₂S, 327.1, found 358.2 [M + Na]⁺.2-(3,4-dimethoxyphenyl)-1-(phenylsulfonyl)- Yield: 60.3%. ¹H NMR (500MHz, CDCl₃) δ 1H-imidazole (10h). 7.64 (d, J = 7.0 Hz, 1 H), 7.55 (t, J= 7.5 Hz, 1 H), 7.40 (dd, J = 8.5 Hz, 1.5 Hz, 2 H), 7.35 (t, J = 8.0 Hz,2H), 7.09 (d, J = 2.0 Hz, 1 H), 7.02 (dd, J = 8.0 Hz, 2.0 Hz, 1 H), 6.89(d, J = 1.5 Hz, 1 H), 6.86 (d, J = 8.0 Hz, 1 H), 3.95 (s, 3 H), 3.81 (s,3 H). MS (ESI): calculated for C₁₇H₁₆N₂O₄S, 344.10, found 367.0 [M +Na]⁺. 1-(phenylsulfonyl)-2-(2- Yield: 58.6%. ¹H NMR (500 MHz, CDCl₃) δ(trifluoromethyl)phenyl)-1H-imidazole (10i). 7.64-7.67 (m, 2 H),7.61-7.63 (m, 3 H), 7.40-7.46 (m, 5 H), 7.16 (d, J = 1.5 Hz, 1 H). MS(ESI): calculated for C₁₆H₁₁F₃N₂O₂S, 352.10, found 353.1 [M + H]⁺.2-(4-(benzyloxy)phenyl)-1-(phenylsulfonyl)- Yield: 62.0%; mp 102-104° C.¹H NMR 1H-imidazole (10j). (500 MHz, CDCl₃) δ 7.56 (d, J = 1.0 Hz, 1 H),7.46 (t, J = 8.0 Hz, 1 H), 7.20-7.40 (m, 11 H), 7.03 (d, J = 1.0 Hz,1H), 6.89 (t, J = 8.0 Hz, 2 H), 5.08 (s, 2 H). MS (ESI): calculated forC₂₂H₁₈N₂O₃S, 390.10, found 413.1 [M + Na]⁺. HPLC2: t_(R) 18.22 min,purity 95.9%. 2-(4-Bromophenyl)-1-(phenylsulfonyl)-1H- Yield: 61.2%. ¹HNMR (500 MHz, CDCl₃) δ imidazole (10la). 7.71 (d, J = 2.0 Hz, 1 H), 7.64(t, J = 7.0 Hz, 1 H), 7.57 (d, J = 9.0 Hz, 2 H), 7.49 (d, J = 7.0 Hz, 2H), 7.45 (t, J = 9.0 Hz, 2 H), 7.34 (d, J = 8.5 Hz, 2 H), 7.18 (d, J =1.5 Hz, 1 H). MS (ESI) calcd for C₁₅H₁₁BrN₂O₂S 362.0, found 363.0 [M +H]⁺. 1-(Phenylsulfonyl)-2-(4- Yield: 36.7%; ¹H NMR (500 MHz, CDCl₃) δ(trifluoromethyl)phenyl)-1H-imidazole (10p). 7.75 (d, J = 2.0 Hz, 1 H),7.69 (d, J = 8.0 Hz, 2 H), 7.65 (t, J = 8.0 Hz, 1 H), 7.60 (d, J = 8.0Hz, 2 H), 7.48 (d, J = 7.5 Hz, 2 H), 7.43 (t, J = 8.0 Hz, 2 H), 7.22 (d,J = 2.0 Hz, 1 H). MS (ESI) calcd for C₁₆H₁₁F₃N₂O₂S 352.1, found 553.1[M + H]⁺. 2-(4-nitrophenyl)-1-(phenylsulfonyl)-1H- Yield: 50%; mp145-147° C. ¹H NMR imidazole (10x). (500 MHz, DMSO-d₆) δ 8.28 (d, J =8.5 Hz, 2 H), 8.03 (d, J = 1.5 Hz, 1 H), 7.78 (t, J = 7.5 Hz, 1 H),7.64-7.68 (m, 4H), 7.60 (t, J = 8.0 Hz, 2 H), 7.30 (d, J = 1.5 Hz, 1 H).MS (ESI): calculated for C₁₅H₁₁N₃O₄S, 329.10, found 352.0 [M + Na]⁺,327.9 [M − H]⁻. HPLC2: t_(R) 14.87 min, purity 98.8%.(4-methoxyphenyl)(2-phenyl-1- Yield: 26.3%; mp 118-120° C. ¹H NMR(phenylsulfonyl)-1H-imidazol-4-yl)methanone (500 MHz, DMSO-d₆) δ 8.37(d, J = 1.0 Hz, 1 (11ab). H), 8.15-8.18 (m, 2 H), 8.12 (d, J = 9.0 Hz, 2H), 7.56-7.64 (m, 5 H), 7.46-7.50 (m, 3 H), 7.16 (d, J = 8.0 Hz, 2 H),3.90 (s, 3 H). MS (ESI): calculated for C₂₃H₁₈N₂O₄S, 418.10, found 419.1[M + H]⁺. HPLC2: t_(R) 17.72 min, purity 95.7%.(3-methoxyphenyl)(2-phenyl-1- Yield: 31.2%; mp 136-138° C. ¹H NMR(phenylsulfonyl)-1H-imidazol-4-yl)methanone (500 MHz, CDCl₃) δ 8.35 (s,1 H), 7.86 (d, J = 8.0 Hz, (11ac). 1 H), 7.72 (s, 1 H), 7.60 (t, J = 7.5Hz, 1 H), 7.51 (t, J = 7.5 Hz, 1 H), 7.35-7.42 (m, 9H), 7.14 (dd, J =8.0 Hz, 2.0 Hz, 1 H), 3.88 (s, 3 H). MS (PSI): calculated forC₂₃H₁₈N₂O₄S, 418.10, found 419.1 [M + H]⁺. HPLC2: t_(R) 17.72 min,purity 95.7%. (2-phenyl-1-(phenylsulfonyl)-1H-imidazol-4- Yield: 28.9%;mp 108-110° C. ¹H NMR yl)(p-tolyl)methanone (11ah) (500 MHz, CDCl₃) δ8.00 (d, J = 7.5 Hz, 2 H), 7.98 (q, J = 8.0 Hz, 1.5 Hz, 2 H), 7.91 (d, J= 8.0 Hz, 1 H), 7.81 (s, 1 H), 7.44-7.48 (m, 3 H), 7.35-7.40 (m, 2 H),7.30 (t, J = 8.0 Hz, 2 H), 7.20 (s, 2 H), 2.42 (s, 3 H). MS (ESI):calculated for C₂₃H₁₈N₂O₃S, 402.10, found 403.1 [M + H]⁺. HPLC2: t_(R)16.06 min, purity 96.2%. (4-fluorophenyl)(2-phenyl-1-(phenylsulfonyl)-Yield: 25.4%; mp 114-116° C. ¹H NMR 1H-imidazol-4-yl)methanone(11af).(500 MHz, CDCl₃) δ 8.10 (q, J = 3.5 Hz, 5.5 Hz, 2 H), 7.88 (d, J = 7.5Hz, 2 H), 7.67 (t, J = 7.5 Hz, 1 H), 7.48-7.54 (m, 3 H), 7.38-7.41 (m, 5H), 7.24 (t, J = 8.5 Hz, 2 H). MS (ESI): calculated for C₂₂H₁₅FN₂O₃S,406.10, found 429.1 [M + Na]⁺. HPLC2: t_(R) 15.43 min, purity 96.1%.(3-fluorophenyl)(2-phenyl-1-(phenylsulfonyl)- Yield: 18.3%; mp 102-104°C. ¹H NMR 1H-imidazol-4-yl)methanone(11ag). (500 MHz, CDCl₃) δ 8.14 (d,J = 7.5 Hz, 1 H), 7.76-7.87 (m, 3 H), 7.74 (d, J = 9.0 Hz, 1 H),7.37-7.57 (m, 10 H), 7.38-7.41 (m, 5 H), 7.24 (t, J = 8.5 Hz, 2 H). MS(ESI): calculated for C₂₂H₁₅FN₂O₃S, 406.10, found 429.1 [M + Na]⁺.HPLC2: t_(R) 15.75 min, purity 96.5%.(4-fluorophenyl)(2-(4-methoxyphenyl)-1- Yield: 23.5%; mp 135-137° C. ¹HNMR (phenylsulfonyl)-1H-imidazol-4-yl)methanone (500 MHz, CDCl₃) δ 8.00(d, J = 5.5 Hz, 2 H), (11cb). 7.74-7.76 (m, 2 H), 7.54-7.58 (m, 1 H),7.40 (d, J = 7.0 Hz, 2 H), 7.28-7.30 (m, 3 H), 7.14-7.16 (m, 2 H),6.80-6.82 (m, 2 H), 3.80 (s, 3 H). MS (ESI): calculated forC₂₃H₁₇FN₂O₄S, 436.10, found 459.0 [M + Na]⁺, 434.9 [M − H]⁻. HPLC2:t_(R) 16.53 min, Purity 96.1%.(1-(Phenylsulfonyl)-2-(p-tolyl)-1H-imidazol- Yield: 33.8%; ¹H NMR (500MHz, CDCl₃) δ 4-yl)(3,4,5-trimethoxyphenyl)methanone 8.00 (d, J = 8.0Hz, 2 H), 7.70 (t, J = 7.5 Hz, 1 (11da). H), 7.55 (t, J = 8.0 Hz, 2 H),7.44 (s, 2 H), 7.34 (s, 2H), 7.31 (d, J = 8.0 Hz, 2 H) , 7.21 (d, J =8.0 Hz, 2 H), 4.00 (s, 3 H), 3.98 (s, 6 H). MS (ESI): calculated forC₂₆H₂₄N₂O₆S, 492.14, found 515.2 [M + Na]⁺.(4-fluorophenyl)(1-(phenylsulfonyl)-2-(p- Yield: 18.6%; mp 142-144° C.¹H NMR tolyl)-1H-imidazol-4-yl)methanone (11db). (500 MHz, CDCl₃) δ 8.07(q, J = 8.5 Hz, 5.5 Hz, 2 H), 7.88 (d, J = 7.5 Hz, 2 H), 7.64 (t, J =8.0 Hz, 1 H), 7.49 (d, J = 8.0 Hz, 2 H), 7.38 (s, 1H), 7.30 (d, J = 8.0Hz, 2 H) , 7.18-7.24 (m, 4 H), 2.43 (s, 3 H). MS (ESI): calculated forC₂₃H₁₇FN₂O₃S, 420.10, found 443.0 [M + Na]⁺, 418.9 [M − H]⁻. HPLC2:t_(R) 17.28 min, purity 97.3%. (1-(phenylsulfonyl)-2-(3,4,5- Yield:21.1%; mp 135-137° C. ¹H NMR trimethoxyphenyl)-1H-imidazol-4-yl)(3,4,5-(500 MHz, CDCl₃) δ 7.91 (d, J = 8.0 Hz, 2 H), trimethoxyphenyl)methanone(11ea). 7.65 (t, J = 7.5 Hz, 1 H), 7.51 (t, J = 8.0 Hz, 2 H), 7.44 (s, 1H), 7.34 (s, 2 H), 6.60 (s, 2 H), 3.98 (s, 3 H), 3.96 (s, 6 H), 3.91 (s,3 H), 3.73 (s, 6 H). MS (ESI): calculated for C₂₈H₂₈N₂O₉S, 568.2, found569.2 [M + H]⁺. HPLC1: t_(R) 17.86 min, purity 98.9%.(4-fluorophenyl)(1-(phenylsulfonyl)-2-(3,4,5- Yield: 18.8%; mp 135-137°C. ¹H NMR trimethoxyphenyl)-1H-imidazol-4- (500 MHz, CDCl₃) δ 8.11 (q, J= 5.5 Hz, 3.0 Hz, yl)methanone (11eb). 1 H), 8.00-8.03 (m, 1 H), 7.82(d, J = 7.5 Hz, 1 H), 7.78 (s, 1 H), 7.64 (t, J = 7.0 Hz, 1 H), 7.48 (t,J = 8.0 Hz, 1 H), 7.42 (s, 1 H), 7.21-7.26 (m, 4 H), 6.62 (s, 1 H), 3.98(s, 3 H), 3.96 (s, 6 H), 3.93 (s, 3 H). MS (ESI): calculated forC₂₅H₂₁FN₂O₆S, 496.10, found 497.1 [M + H]⁺. HPLC2: t_(R) 15.26 min,purity 98%. (2-(4-chlorophenyl)-1-(phenylsulfonyl)-1H- Yield: 36.8%; mp153-155° C. ¹H NMR imidazol-4-yl)(4-fluorophenyl)methanone (500 MHz,CDCl₃) δ 8.06 (q, J = 5.5 Hz, 3.0 Hz, (11fb). 2 H), 7.89 (d, J = 7.5 Hz,2 H), 7.68 (t, J = 8.0 Hz, 1 H), 7.52 (t, J = 8.0 Hz, 2 H), 7.34-7.38(m, 5H), 7.23 (t, J = 8.5 Hz, 2 H). MS (ESI): calculated forC₂₂H₁₄ClFN₂O₃S, 440.0, found 463.0 [M + Na]⁺. HPLC2: t_(R) 17.72 min,purity 97.38%. (2-(4-(dimethylamino)phenyl)-1- Yield: 32.2%; mp 157-159°C. ¹H NMR (phenylsulfonyl)-1H-imidazol-4-yl)(3,4,5- (500 MHz, CDCl₃) δ7.89 (d, J = 8.0 Hz, 2 H), trimethoxyphenyl)methanone (11ga). 7.62 (t, J= 7.5 Hz, 1 H), 7.48 (t, J = 8.0 Hz, 2 H), 7.43 (s, 1 H), 7.32 (d, J =8.5 Hz, 2 H), 7.30 (s, 2H), 6.62 (d, J = 9.0 Hz, 2 H), 3.97 (s, 3 H),3.95 (s, 6 H), 3.05 (s, 6 H). MS (ESI): calculated for C₂₇H2₇N₃O₆S,521.2, found 544.1 [M + Na]⁺, 519.8 [M − H]⁻. HPLC2: t_(R) 16.00 min,purity 97.9%. (2-(4-(dimethylamino)phenyl)-1- Yield: 38.5%; mp 125-127°C. ¹H NMR (phenylsulfonyl)-1H-imidazol-4-yl)(4- (500 MHz, CDCl₃) δ 8.04(q, J = 5.5 Hz, 3.5 Hz, fluorophenyl)methanone (11gb). 2 H), 7.80 (d, J= 7.5 Hz, 2 H), 7.61 (t, J = 8.0 Hz, 1 H), 7.45 (t, J = 8.0 Hz, 2 H),7.39 (s, 1 H), 7.35 (d, J = 9.0 Hz, 2 H), 7.21 (t, J = 8.5 Hz, 2 H),6.62 (d, J = 9.0 Hz, 2 H), 3.05 (s, 6 H). MS (ESI): calculated forC₂₄H₂₀FN₃O₃S, 449.10, found 472.1 [M + Na]⁺, 447.9 [M − H]⁻. HPLC2:t_(R) 16.85 min, purity 96.5%.(2-(3,4-dimethoxyphenyl)-1-(phenylsulfonyl)- Yield: 28.6%; mp 136-138°C. ¹H NMR 1H-imidazol-4-yl)(3,4,5- (300 MHz, CDCl₃) δ 7.92 (dd, J = 8.5Hz, 1.5 Hz, trimethoxyphenyl)methanone (11ha). 2 H), 7.66 (t, J = 7.5Hz, 2 H), 7.51 (t, J = 7.5 Hz, 2 H), 7.43 (s, 1 H), 7.33 (s, 2 H), 7.02(dd, J = 8.0 Hz, 2.0 Hz, 1 H), 6.91 (d, J = 2.0 Hz, 1 H), 6.86 (d, J =8.5 Hz, 1 H), 3.98 (s, 3 H), 3.96 (s, 9 H), 3.77 (s, 3 H). MS (ESI):calculated for C₂₇H₂₆N₂O₈S, 538.10, found 561.1 [M + Na]⁺, 536.8 [M −H]⁻. HPLC2: t_(R) 14.67 min, purity 98.2%.(2-(3,4-dimethoxyphenyl)-1-(phenylsulfonyl)- Yield: 31.9%; mp 144-145°C. ¹H NMR 1H-imidazol-4-yl)(4-fluorophenyl)methanone (300 MHz, CDCl₃) δ8.09 (q, J = 5.5 Hz, 3.5 Hz, (11hb). 2 H), 7.81 (d, J = 8.0 Hz, 2 H),7.62 (t, J = 7.5 Hz, 2 H), 7.48 (t, J = 7.5 Hz, 2 H), 7.40 (s, 1 H),7.21-7.25 (m, 2 H), 7.04 (dd, J = 8.0 Hz, 2.0 Hz, 1 H), 6.92 (d, J = 2.0Hz, 1 H), 6.86 (d, J = 8.5 Hz, 1 H), 3.96 (s, 3 H), 3.79 (s, 6 H). MS(ESI): calculated for C₂₄H₁₉FN₂O₅S, 466.10, found 489.1 [M + Na]⁺, 464.8[M − H]⁻. HPLC2: t_(R) 15.52 min, purity 97.4%.(1-(phenylsulfonyl)-2-(2- Yield: 25.0%; mp 155-157° C. ¹H NMR(trifluoromethyl)phenyl)-1H-imidazol-4- (500 MHz, DMSO-d₆) δ 7.91 (d, J= 8.0 Hz, 1 yl)(3,4,5-trimethoxyphenyl)methanone (11ia). H), 7.84 (q, J= 7.5 Hz, 5.0 Hz, 2 H), 7.77-7.80 (m, 2 H), 7.75 (s, 2 H), 7.66 (t, J =8.0 Hz, 2 H), 7.56 (d, J = 7.5 Hz, 1 H), 7.18 (s, 2 H), 3.87 (s, 6 H),3.81 (s, 3 H). MS (ESI): calculated for C₂₆H₂₁F₃N₂O₆S, 546.10, found569.0 [M + Na]⁺. HPLC2: t_(R) 16.16 min, purity 98.9%.(1-(phenylsulfonyl)-2-(2- Yield: 25.0%; mp 151-153° C. ¹H NMR(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(4- (500 MHz, CDCl₃) δ 8.03(q, J = 5.5 Hz, 3.0 Hz, fluorophenyl)methanone (11ib). 2 H), 7.90 (d, J= 8.0 Hz, 2 H), 7.80 (d, J = 8.0 Hz, 1 H), 7.69 (q, J = 7.0 Hz, 6.5 Hz,2 H), 7.61 (t, J = 8.0 Hz, 1 H), 7.52 (t, J = 8.0 Hz, 2 H), 7.34-7.36(m, 2 H), 7.23 (t, J = 8.5 Hz, 2 H). MS (ESI): calculated forC₂₃H₁₄F₄N₂O₃S, 474.10, found 497.0 [M + Na]⁺. HPLC2: t_(R) 16.80 min,purity 98.2%. (2-(4-(benzyloxy)phenyl)-1-(phenylsulfonyl)- Yield:22.3.0%; mp 149-151° C. ¹H NMR1H-imidazol-4-yl)(4-fluorophenyl)methanone (500 MHz, CDCl₃) δ 8.09 (q, J= 5.5 Hz, 3.5 Hz, (11jb). 2 H), 7.82 (d, J = 7.5 Hz, 2 H), 7.63 (t, 7.5Hz, 1 H), 7.36-7.50 (m, 10 H), 7.25 (t, J = 8.5 Hz, 2 H), 6.98 (d, J =8.0 Hz, 2 H), 5.17 (s, 2 H). MS (ESI): calculated for C₂₉H₂₁FN₂O₄S,512.10, found 535.0 [M + Na]⁺. HPLC2: t_(R) 18.35 min, purity 95.1%.(2-(4-Bromophenyl)-1-(phenylsulfonyl)-1H- Yield: 32.6% ¹H NMR (500 MHz,CDCl₃) δ imidazol-4-yl)(3,4,5- 8.06 (d, J = 8.0 Hz, 2 H), 7.88 (d, J =8.5 Hz, 1 trimethoxyphenyl)methanone (11la). H), 7.77 (t, J = 7.0 Hz, 1H), 7.54-7.63 (m, 4 H), 7.31-7.36 (m, 4 H), 4.04 (s, 3 H), 4.01 (s, 6H). MS (ESI) calcd for C₂₅H₂₁BrN₂O₆S 556.0, found 557.0 [M + H]⁺.(1-(Phenylsulfonyl)-2-(4- Yield: 36.7%; ¹H NMR (500 MHz, CDCl₃) δ(trifluoromethyl)phenyl)-1H-imidazol-4- 8.06 (d, J = 7.5 Hz, 2 H), 7.78(t, J = 8.0 Hz, 1 yl)(3,4,5-trimethoxyphenyl)methanone (11pa). H), 7.72(d, J = 8.0 Hz, 2 H), 7.62 (d, J = 8.0 Hz, 2 H), 7.59 (d, J = 8.0 Hz, 2H), 7.50 (s, 1 H), 7.37 (s, 2 H), 4.04 (s, 3 H), 4.02 (s, 6 H). MS (ESI)calcd for C₂₆H₂₁F₃N₂O₆S 546.1, found 547.1 [M + H]⁺.(2-(4-(Dimethylamino)phenyl)-1-((4- Yield: 34.1%; mp 147-149° C. ¹H NMR(500 MHz, methoxyphenyl)sulfonyl)-1H-imidazol-4- CDCl₃) δ 8.07 (q, J =8.5 Hz, 5.5 Hz, 2 yl)(3,4,5-trimethoxyphenyl)methanone H), 7.78 (d, J =9.0 Hz, 2 H), 7.41 (d, J. 8.5 Hz, (11gaa). 2 H), 7.39 (s, 1 H), 7.23 (t,J = 8.5 Hz, 2 H), 6.91 (d, J = 9.0 Hz, 2 H), 6.68 (d, J = 9.0 Hz, 2 H),3.89 (s, 3 H), 3.08 (s, 3 H). MS (ESI) calcd for C₂₈H₂₉N₃O₇S 551.2,found 573.1 [M + Na]⁺. HPLC2: t_(R) 18.6 min, purity 96.9%.(2-phenyl-1H-imidazol-4-yl)(3,4,5- Yield: 10.1%; mp 227-229° C. ¹H NMRtrimethoxyphenyl)methanone (12aa). (500 MHz, CDCl₃) δ 8.0-8.03 (m, 2 H),7.83 (s, 1 H), 7.34-7.38 (m, 3 H), 7.21 (s, 2 H), 3.90 (s, 3 H), 3.84(s, 6 H). MS (ESI): calculated for C₁₉H₁₈N₂O, 338.1, found 337.1 [M −H]⁻. HPLC2: t_(R)14.19 min, purity 96.3%.(4-methoxyphenyl)(2-phenyl-1H-imidazol-4- Yield: 16.6%; mp 179-181° C.¹H NMR yl)methanone (12ab). (500 MHz, CDCl₃) δ 11.1 (br, 1 H), 8.07-8.10(m, 2 H), 8.04 (d, J = 8.5 Hz, 2 H), 7.84 (d, J = 1.0 Hz, 1 H),7.49-7.51 (m, 3 H), 7.07 (d, J = 9.0 Hz, 2 H), 3.95 (s, 3 H). MS (ESI):calculated for C₁₇H₁₄N₂O₂, 278.10, found 279.0 [M + H]⁺. HPLC1: t_(R)15.14 min, purity >99%. (3-methoxyphenyl)(2-phenyl-1H-imidazol-4- Yield:22.5%; mp 160-162° C. ¹H NMR yl)methanone (12ac). (500 MHz, CDCl₃) δ11.2 (br, 1 H), 8.10-8.12 (m, 2 H), 7.87 (d, J = 1.0 Hz, 1 H), 7.61 (d,J = 7.5 Hz, 1 H), 7.48-7.52 (m, 5 H), 7.21 (dd, J = 2.5 Hz, 8.5 Hz, 1H), 3.91 (s, 3 H). MS (ESI): calculated for C₁₇H₁₄N₂O₂, 278.10, found279.0 [M + H]⁺. HPLC2: t_(R) 15.07 min, purity >99%.(3,5-dimethoxyphenyl)(2-phenyl-1H- Yield: 26.2%; mp 168-170° C. ¹H NMRimidazol-4-yl)methanone (12ad). (500 MHz, CDCl₃) δ 8.04-8.06 (m, 2 H),7.88 (s, 1 H), 7.50-7.52 (m, 3 H), 7.15 (d, J = 2.0 Hz, 2 H), 6.75 (t, J= 1.0 Hz, 1 H), 3.89 (s, 6 H). MS (ESI): calculated for C₁₈H₁₆N₂O₃,308.10, found 331.1 [M + Na]⁺, 306.9 [M − H]⁻. HPLC2: t_(R) 15.59 min,purity >99%. (3,4-dimethoxyphenyl)(2-phenyl-1H- Yield: 18.6%; mp162-164° C. ¹H NMR imidazol-4-yl)methanone (12ae). (500 MHz, CDCl₃) δ10.9 (br, 1 H), 8.05 (dd, J = 1.5 Hz, 8.0 Hz, 2 H), 7.86 (d, J = 1.5 Hz,1 H), 7.74 (dd, J = 2.0 Hz, 8.5 Hz, 1 H), 7.56 (d, J = 2.0 Hz, 1 H),7.50-7.52 (m, 3 H), 7.04 (d, J = 8.5 Hz, 1 H), 4.03 (s, 3 H), 3.99 (s, 3H). MS (ESI): calculated for C₁₈H₁₆N₂O₃, 308.10, found 331.1 [M + Na]⁺,306.9 [M − H]⁻. HPLC2: t_(R) 13.54 min, purity >99%.(4-fluorophenyl)(2-phenyl-1H-imidazol-4- Yield: 30.2%; mp 231-233° C. ¹HNMR yl)methanone (12af). (500 MHz, CDCl₃) δ 10.6 (br, 1 H), 8.02-8.05(m, 4 H), 7.81 (d, J = 1.0 Hz, 1 H), 7.51-7.54 (m, 3 H), 7.27 (t, J =8.5 Hz, 2 H). MS (ESI): calculated for C₁₆H₁₁FN₂O, 266.10, found 267.0[M + H]⁺, 264.8 [M − H]⁻. HPLC1: t_(R) 15.37 min, purity 98.9%.(3-fluorophenyl)(2-phenyl-1H-imidazol-4- Yield: 23.4%; mp 212-214° C. ¹HNMR yl)methanone (12ag). (500 MHz, CDCl₃) δ 8.05 (dd, J = 1.5 Hz, 7.5Hz, 2 H), 7.86 (s, 1 H), 7.84 (d, J = 7.0 Hz, 1 H), 7.74 (d, J = 8.5 Hz,1 H), 7.52-7.58 (m, 4 H), 7.37 (dt, J = 2.0 Hz, 6.0 Hz, 1 H). MS (ESI):calculated for C₁₆H₁₁FN₂O, 266.10, found 267.0 [M + H]⁺, 264.8 [M − H]⁻.HPLC1: t_(R) 15.29 min, purity >99%. (2-phenyl-1H-imidazol-4-yl)(p-Yield: 15.6%; mp 225-227° C. ¹H NMR tolyl)methanone (12ah). (500 MHz,CDCl₃) δ 11.1 (br, 1 H), 8.08 (d, J = 7.5 Hz, 2 H), 7.93 (d, J = 9.0 Hz,2 H), 7.84 (s, 1 H), 7.48-7.52 (m, 3 H), 7.38 (d, J = 10.0 Hz, 2 H),2.50 (s, 3 H). MS (ESI): calculated for C₁₇H₁₄N₂O, 262.10, found 263.0[M + H]⁺, 260.8 [M − H]⁻. HPLC2: t_(R) 15.86 min, purity 98.7%.(2-phenyl-1H-imidazol-4-yl)(m- Yield: 20.5%; mp 168-169° C. ¹H NMRtolyl)methanone (12ai). (500 MHz, CDCl₃) δ 11.0 (br, 1 H), 8.09-8.11 (m,2 H), 7.84 (d, J = 1.5 Hz, 1 H), 7.81-7.82 (m, 2 H), 7.47-7.52 (m, 5 H),2.50 (s, 3 H). MS (ESI): calculated for C₁₇H₁₄N₂O, 262.10, found 285.0[M + Na]⁺, 260.8 [M − H]⁻. HPLC2: t_(R) 15.89 min, purity >99%.(2-(4-fluorophenyl)-1H-imidazol-4-yl)(3,4,5- Yield: 12.2%. mp 176-178°C. ¹H NMR trimethoxyphenyl)methanone (12ba). (500 MHz, CDCl₃) δ 10.72(br, 1 H), 8.02 (q, J = 5.0 Hz, 2 H), 7.84 (s, 1 H), 7.19 (t, J = 10.0Hz, 2 H), 4.00 (s, 6 H), 3.97 (s, 3 H). MS (ESI): calculated forC₁₉H₁₇FN₂O₄, 356.10, found 379.1 [M + Na]⁺, 354.9 [M − H]⁻. HPLC1: t_(R)17.23 min, purity >99% (2-(4-methoxyphenyl)-1H-imidazol-4- Yield: 10.2%;mp 220-222° C. ¹H NMR yl)(3,4,5-trimethoxyphenyl)methanone (12ca). (300MHz, CDCl₃) δ 10.24 (br, 1 H), 7.93 (d, J = 14.5 Hz, 2 H), 7.81 (s, 1H), 7.24 (s, 2 H), 7.03 (d, J = 14.5 Hz, 2 H), 3.97 (s, 3 H), 3.95 (s, 6H), 3.90 (s, 3 H). MS (ESI): calculated for C₂₀H₂₀N₂O₅, 368.10, found391.0 [M + Na]⁺, 367.0 [M − H]⁻. HPLC2: t_(R) 14.46 min, purity 98.4%.(4-fluorophenyl)(2-(4-methoxyphenyl)-1H- Yield: 15.2%; mp 245-247° C. ¹HNMR imidazol-4-yl)methanone (12cb). (500 MHz, CDCl₃) δ 10.20 (br, 1 H),7.93-7.96 (m, 2 H), 7.85 (d, J = 5.0 Hz, 2 H), 7.68 (s, 1 H), 7.15-7.17(m, 2 H), 6.95 (d, J = 6.0 Hz, 2 H), 3.82 (s, 3 H). MS (ESI): calculatedfor C₁₇H₁₃FN₂O₂, 296.10, found 319.1 [M + Na]⁺, 294.9 [M − H]⁻. HPLC2:t_(R) 15.40 min, purity 98.8%. (2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-Yield: 48.5%; mp 201-203° C. ¹H NMR trimethoxyphenyl)methanone (12da).(500 MHz, CDCl₃) δ 10.40 (br, 1 H), 7.88 (d, J = 8.0 Hz, 2 H), 7.82 (s,1 H), 7.31 (d, J = 8.0 Hz, 2 H), 7.24 (s, 2 H), 3.96 (s, 3 H), 3.94 (s,6 H), 2.43 (s, 3 H). MS (ESI): calculated for C₂₀H₂₀N₂O₄, 352.10, found375.2 [M + Na]⁺. HPLC2: t_(R) 15.45 min, purity 97.4%.(4-fluorophenyl)(2-(p-tolyl)-1H-imidazol-4- Yield: 56.3%; mp 229-231° C.¹H NMR yl)methanone (12db). (500 MHz, CDCl₃) δ 10.50 (br, 1 H),7.99-8.02 (m, 2 H), 7.88 (d, J = 8.0 Hz, 2 H), 7.60 (d, J = 1.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 2 H), 7.23 (t, J = 9.0 Hz, 2 H), 2.43 (s, 3 H).MS (ESI): calculated for C₁₇H₁₃FN₂O, 280.10, found 281.0 [M + H]⁺, 278.9[M − H]⁻. HPLC2: t_(R) 16.31 min, purity >99%.(4-hydroxy-3,5-dimethoxyphenyl)(2-(p-tolyl)- Yield: 56.8%; mp 220-222°C. ¹H NMR (500 MHz, 1H-imidazol-4-yl)methanone (12dc). CDCl₃) δ 8.02 (d,J = 8.0 Hz, 2H), 7.91 (s, 1H), 7.39 (s, 2H), 7.28 (d, J = 7.5 Hz, 2H),4.00 (s, 6H), 2.44 (s, 3H). MS (ESI) calcd for C₁₉H₁₈FN₂O₄ 338.1, found339.1 [M + H]⁺. HPLC1: t_(R) 3.91 min, purity >99%.(3,4,5-trimethoxyphenyl)(2-(3,4,5- Yield: 86.8%; mp 196-198° C. ¹H NMRtrimethoxyphenyl)-1H-imidazol-4- (500 MHz, DMSO-d₆) δ 13.3 (br, 0.47 H),yl)methanone (12ea). 13.50 (br, 0.52 H), 8.19 (s, 0.49 H), 7.90 (s, 1H), 7.83 (s, 0.5 H), 7.59 (s, 1 H), 7.40 (s, 1 H), 7.18 (s, 1 H), 3.89(s, 6 H), 3.86 (s, 6 H), 3.77 (s, 3 H), 3.72 (s, 3 H). MS (ESI):calculated for C₂₂H₂₄N₂O₇, 428.2, found 451.1 [M + Na]⁺, 426.9 [M − H]⁻.HPLC2: t_(R) 14.49 min, purity >99%.(4-fluorophenyl)(2-(3,4,5-trimethoxyphenyl)- Yield: 90.2%; mp 153-155°C. ¹H NMR 1H-imidazol-4-yl)methanone (12eb). (500 MHz, CDCl₃) δ 10.42(br, 1 H), 8.00 (q, J = 5.5 Hz, 3.0 Hz, 2 H), 7.76 (s, 1 H), 7.23 (t, J= 8.5 Hz, 2 H), 7.19 (s, 2 H), 3.94 (s, 3 H), 3.92 (s, 3 H). MS (ESI):calculated for C₁₉H₁₇FN₂O₄, 356.1, found 379.0 [M + Na]⁺, 354.9 [M −H]⁻. HPLC2: t_(R) 15.31 min, purity >99%.(2-(4-chlorophenyl)-1H-imidazol-4-yl)(3,4,5- Yield: 36.9%; mp 193-195°C. ¹H NMR trimethoxyphenyl)methanone (12fa). (500 MHz, CDCl₃) δ 10.75(br, 1 H), 7.96 (d, J = 8.5 Hz, 2 H), 7.83 (s, 1 H), 7.47 (d, J = 9.0Hz, 2 H), 7.23 (s, 2 H), 3.97 (s, 3 H), 3.94 (s, 6 H), 2.43 (s, 3 H). MS(ESI): calculated for C₁₉H₁₇ClN₂O₄, 372.1, found 395.1 [M + Na]⁺, 370.9[M − H]⁻. HPLC2: t_(R) 16.36 min, purity >99%.(2-(4-chlorophenyl)-1H-imidazol-4-yl)(4- Yield: 83.7%; mp 232-234° C. ¹HNMR fluorophenyl)methanone (12fb). (500 MHz, CDCl₃) δ 10.78 (br, 1 H),8.00 (q, J = 5.5 Hz, 3.0 Hz, 2 H), 7.96 (d, J = 9.0 Hz, 2 H), 7.78 (s, 1H), 7.47 (d, J = 8.0 Hz, 2 H), 7.24 (t, J = 8.5 Hz, 2 H). MS (ESI):calculated for C₁₆H₁₀ClFN₂O, 300.1, found 323.0 [M + Na]⁺, 298.8 [M −H]⁻. HPLC2: t_(R) 17.08 min, purity >99%.(2-(4-chlorophenyl)-1H-imidazol-4-yl)(4- Yield: 80.2%; mp 216-218° C. ¹HNMR (500 MHz, hydroxy-3,5-dimethoxyphenyl)methanone CD₃OD) δ 8.06 (d, J= 8.5 Hz, 2 H), (12fc). 7.99 (s, 1 H), 7.61 (d, J = 8.0 Hz, 2 H), 7.52(s, 2 H), 4.01 (s, 6 H). MS (ESI) calcd for C₁₈H₁₅ClN₂O₄ 358.1, found359.1 [M + H]⁺. HPLC2: t_(R) 4.12 min, purity >99%.(2-(4-(dimethylamino)phenyl)-1H-imidazol-4- Yield: 91.2%; mp 195-197° C.¹H NMR yl)(3,4,5-trimethoxyphenyl)methanone (12ga). (500 MHz, CDCl₃) δ10.39 (br, 1 H), 7.87 (d, J = 8.5 Hz, 2 H), 7.80 (s, 1 H), 7.23 (s, 2H), 6.75 (d, J = 9.0 Hz, 2 H), 3.95 (s, 3 H), 3.94 (s, 6 H), 3.05 (s, 6H). MS (ESI): calculated for C₂₁H₂₃N₃O₄, 381.2, found 404.2 [M + Na]⁺,380.0 [M − H]⁻. HPLC2: t_(R) 15.20 min, purity 95.8%.(2-(4-(dimethylamino)phenyl)-1H-imidazol-4- Yield: 86.7%; mp 278-280° C.¹H NMR yl)(4-fluorophenyl)methanone (12gb). (500 MHz, CDCl₃) δ 10.21(br, 1 H), 7.98 (q, J = 5.0 Hz, 3.5 Hz, 2 H), 7.84 (d, J = 8.5 Hz, 2 H),7.72 (s, 1 H), 7.20 (t, J = 8.5 Hz, 2 H), 6.76 (t, J = 9.0 Hz, 2 H),3.06 (s, 6 H). MS (ESI): calculated for C₁₈H₁₆FN₃O, 309.1, found 332.1[M + Na]⁺, 307.9 [M − H]⁻. HPLC2: t_(R) 16.06 min, purity 95.6%.(2-(3,4-dimethoxyphenyl)-1H-imidazol-4- Yield: 85.0%; mp 100-102° C. ¹HNMR yl)(3,4,5-trimethoxyphenyl)methanone (12ha). (500 MHz, CDCl₃) δ10.19 (br, 1 H), 7.81 (s, 1 H), 7.58 (d, J = 1.5 Hz, 1 H), 7.48 (d, J =8.0 Hz, 1 H), 7.25 (s, 2 H), 6.97 (d, J = 8.5 Hz, 1 H), 4.00 (s, 3 H),3.96 (s, 6 H), 3.95 (s, 6 H). MS (ESI): calculated for C₂₁H₂₂N₂O₆,398.2, found 399.1 [M + H]⁺, 397.0 [M − H]⁻. HPLC2: t_(R) 13.73 min,purity >99%. (2-(3,4-dimethoxyphenyl)-1H-imidazol-4- Yield: 78.3%; mp174-176° C. ¹H NMR yl)(4-fluorophenyl)methanone (12hb). (500 MHz, CDCl₃)δ 8.02 (t, J = 9.0 Hz, 2 H), 7.75 (s, 1 H), 7.57 (s, 1 H), 7.48 (d, J =8.5 Hz, 1 H), 7.23 (t, J = 8.5 Hz, 2 H), 6.95 (d, J = 8.5 Hz, 1 H), 3.99(s, 3 H), 3.96 (s, 3 H). MS (ESI): calculated for C₁₈H₁₅FN₂O₃, 326.1,found 349.0 [M + Na]⁺, 324.9 [M − H]⁻. HPLC2: t_(R) 14.65 min,purity >99%. (2-(2-(trifluoromethyl)phenyl)-1H-imidazol-4- Yield: 83.8%;mp 75-77° C. ¹H NMR yl)(3,4,5-trimethoxyphenyl)methanone (12ia). (500MHz, CDCl₃) δ 10.37 (br, 1 H), 8.00-8.02 (m, 1 H), 7.87 (s, 1 H),7.82-7.85 (m, 1 H), 7.69-7.74 (m, 1 H), 7.62-7.66 (m, 1 H), 7.25 (s, 2H), 3.99 (s, 3 H), 3.98 (s, 6 H). MS (ESI): calculated for C₂₀H₁₇F₃N₂O₄,406.1, found 429.1 [M + Na]⁺, 405.0 [M − H]⁻. HPLC2: t_(R) 13.98 min,purity >99%. (4-fluorophenyl)(2-(2- Yield: 91.1%; mp 152-154° C. ¹H NMR(trifluoromethyl)phenyl)-1H-imidazol-4- (500 MHz, CDCl₃) δ 8.12-8.14 (m,2 H), 7.97 (d, yl)methanone (12ib). J = 7.5 Hz, 1 H), 7.82-7.85 (m, 2H), 7.69 (t, J = 7.5 Hz, 1 H), 7.61 (t, J = 8.0 Hz, 1 H), 7.22 (t, J =9.0 Hz, 2 H). MS (ESI): calculated for C₁₇H₁₀F₄N₂O, 334.1, found 357.1[M + Na]⁺, 332.9 [M − H]⁻. HPLC2: t_(R) 15.10 min, purity >99%.(2-(4-(benzyloxy)phenyl)-1H-imidazol-4- Yield: 16.5%; mp 191-193° C. ¹HNMR yl)(3,4,5-trimethoxyphenyl)methanone (12ja). (500 MHz, CDCl₃) δ10.22 (br, 1 H), 7.93 (d, J = 9.0 Hz, 2 H), 7.81 (s, 1 H), 7.37-7.47 (m,5 H), 7.24 (s, 2 H), 7.11 (d, J = 8.5 Hz, 2 H), 5.16 (s, 2 H), 3.97 (s,3 H), 3.95 (s, 6 H). MS (ESI): calculated for C₂₆H₂₄N₂O₅, 444.2, found467.1 [M + Na]⁺, 442.9 [M − H]⁻. HPLC2: t_(R) 17.36 min, purity 95.5%.(2-(4-(benzyloxy)phenyl)-1H-imidazol-4- Yield: 84.7%; mp 212-214° C. ¹HNMR yl)(4-fluorophenyl)methanone (12jb). (300 MHz, CDCl₃) δ 10.28 (br, 1H), 799-8.04 (m, 2 H), 7.92-7.95 (m, 2 H), 7.76 (d, J = 1.5 Hz, 1 H),7.38-7.48 (m, 5 H), 7.20-7.25 (m, 2 H), 7.09-7.12 (m, 2 H), 5.16 (s, 2H). MS (ESI): calculated for C₂₃H₁₇FN₂O₂, 372.1, found 395.1 [M + Na]⁺.HPLC2: t_(R) 17.97 min, purity 97.8%.(2-(4-hydroxyphenyl)-1H-imidazol-4- Yield: 72.3%. mp 191-193° C. ¹H NMRyl)(3,4,5-trimethoxyphenyl)methanone (12ka). (500 MHz, CD₃OD) δ 8.31 (s,1 H), 7.90 (d, J = 8.5 Hz, 2 H), 7.31 (s, 2 H), 7.05 (s, 2 H), 3.95 (s,6 H), 3.88 (s, 3 H). MS (ESI): calculated for C₁₉H₁₈N₂O₅, 354.1, found355.1 [M + H]⁺, 352.9 [M − H]⁻. HPLC2: t_(R) 12.25 min, purity 98.7%.(2-(4-(hydroxyphenyl)-1H-imidazol-4-yl)(4- Yield: 89.0%; mp 276-278° C.¹H NMR fluorophenyl)methanone (12kb). (500 MHz, CDCl₃) δ 8.31 (s, 1 H),8.13 (q, J = 5.5 Hz, 3.0 Hz, 2 H), 7.93 (d, J = 8.5 Hz, 2 H), 7.38 (t, J= 8.5 Hz, 2 H), 7.07 (d, J = 8.5 Hz, 2 H). MS (ESI): calculated forC₁₆H₁₁FN₂O₂, 282.1, found 283.0 [M + H]⁺, 280.9 [M − H]⁻. HPLC2: t_(R)13.46 min, purity 97.65%. (2-(4-bromophenyl)-1H-imidazol-4-yl)(3,4,5-Yield: 25.6%; mp 190-192° C. ¹H NMR (500 MHz, trimethoxyphenyl)methanone(12la). CDCl₃) δ 7.99 (d, J = 8.5 Hz, 2 H), 7.92 (s, 1 H), 7.70 (d, J =8.5 Hz, 2 H), 7.32 (s, 2 H), 4.03 (s, 3 H), 4.00 (s, 6 H). MS (ESI)calcd for C₁₉H₁₇BrN₂O₄ 416.0, found 417.0 [M + H]⁺. HPLC2: t_(R) 4.24min, purity 98.8%. (2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4- Yield:85.3%; mp 195-196° C. ¹H NMR (500 MHz,yl)(3,4,5-trimethoxyphenyl)methanone (12pa). CDCl₃) δ 8.22 (d, J = 8.5Hz, 2 H), 7.96 (s, 1 H), 7.83 (d, J = 8.5 Hz, 2 H), 7.34 (s, 2 H), 4.04(s, 3 H), 4.00 (s, 6 H). MS (ESI) calcd for C₂₀H₁₇F₃N₂O₄ 406.1, found407.1 [M + H]⁺, HPLC2: t_(R) 18.00 min, purity >99%.(2-phenyl-1H-imidazol-1-yl)(3,4,5- Yield: 39.8%; mp 113-115° C. ¹H NMRtrimethoxyphenyl)methanone (12aaa). (500 MHz, CDCl₃) δ 7.53 (q, J = 5.0Hz, 3.0 Hz, 2 H), 7.41 (d, J = 1.0 Hz, 1 H), 7.33-7.35 (m, 3 H), 7.23(d, J = 1.0 Hz, 1 H), 7.03 (s, 2 H), 3.93 (s, 3 H), 3.85 (s, 6 H). MS(ESI): calculated for C₁₉H₁₈N₂O₄, 338.1, found 339.1 [M + H]⁺. HPLC2:t_(R) 13.8 min, purity 95.6%. (4-methoxyphenyl)(2-phenyl-1H-imidazol-1-Yield: 56.3%; mp 68-70° C. ¹H NMR yl)methanone (12aba). (500 MHz, CDCl₃)δ 7.78 (d, J = 9.0 Hz, 2 H), 7.54-7.56 (m, 2 H), 7.32-7.34 (m, 4 H),7.21 (d, J = 1.0 Hz, 1 H), 6.93 (d, J = 8.5 Hz, 2 H), 3.90 (s, 3 H). MS(ESI): calculated for C₁₇H₁₄N₂O₂, 278.1, found 301.0 [M + Na]⁺, 276.8 [M− H]⁻. HPLC2: t_(R) 14.72 min, purity 95.7%.(4-fluorophenyl)(2-(p-tolyl)-1H-imidazol-4- Yield: 95%; mp 115-117° C.¹H NMR yl)methanone HCl salt (12db-HCl). (500 MHz, DMSO-d₆) δ 8.20-8.23(m, 2 H), 8.18 (s, 1 H), 8.04 (d, J = 6.5 Hz, 2 H), 7.42 (t, J = 8.0 Hz,2 H), 7.37 (d, J = 7.0 Hz, 2 H), 2.38 (s, 3 H). MS (ESI): calculated forC₁₇H₁₄FClN₂O, 316.1, found 281.0 [M − HCl + H]⁺. HPLC2: t_(R) 17.16 min,purity >99%. (4-fluorophenyl)(2-(4-methoxyphenyl)-1- Yield: 90.2%; mp148-150° C. ¹H NMR (500 MHz, methyl-1H-imidazol-4-yl)methanone (12cba).CDCl₃) δ 8.45 (q, J = 8.5 Hz, 5.5 Hz, 2 H), 7.79 (s, 1 H), 7.63 (d, J =8.5 Hz, 2 H), 7.16 (t, J = 8.5 Hz, 2 H), 7.03 (d, J = 9.0 Hz, 2 H), 3.89(s, 3 H), 3.82 (s, 3 H). MS (ESI) calcd for C₁₈H₁₅FN₂O₂ 310.1, found311.0 [M + H]⁺. HPLC2: t_(R) 4.01 min, purity 97.6%.(1-benzyl-2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5- Yield: 92.8%; mp 135-137°C. ¹H NMR (500 MHz, trimethoxyphenyl)methanone (12daa). CDCl₃) δ 7.81(s, 1 H), 7.80 (d, J = 6.5 Hz, 2 H), 7.58 (d, J = 8.0 Hz, 2 H),7.41-7.45 (m, 3 H), 7.31-7.33 (m, 2 H), 7.20 (d, J = 7.0 Hz, 2 H), 5.33(s, 2 H), 3.99 (s, 3 H), 3.98 (s, 6 H), 2.47 (s, 3 H). MS (ESI) calcdfor C₂₇H₂₆N₂O₄ 442.2, found 443.1 [M + Na]⁺. HPLC1: t_(R) 4.28 min,purity >99%. (1-methyl-2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5- Yield:87.4%; mp 110-112° C. ¹H NMR (500 MHz, trimethoxyphenyl)methanone(12dab). CDCl₃) δ 7.87 (s, 2 H), 7.86 (d, J = 8.0 Hz, 1 H), 7.65 (d, J =10 Hz, 2 H), 7.37 (d, J = 10 Hz, 2 H), 4.01 (s, 6 H), 4.00 (s, 3 H),3.90 (s, 3 H). MS (ESI) calcd for C₂₁H₂₂N₂O₄ 366.2, found 367.2 [M +H]⁺. HPLC1: t_(R) 4.23 min, purity >99%.(2-(4-(dimethylamino)phenyl)-1-((4- Yield: 34.1%; mp 147-149° C. ¹H NMRmethoxyphenyl)sulfonyl)-1H-imidazol-4- (CDCl₃, 500 MHz) δ 8.07 (q, J =8.5 Hz, 5.5 Hz, yl)(4-fluorophenyl)methanone (12gba). 2 H), 7.78 (d, J =9.0 Hz, 2 H), 7.41 (d, J = 8.5 Hz, 2 H), 7.39 (s, 1 H), 7.23 (t, J = 8.5Hz, 2 H), 6.91 (d, J = 9.0 Hz, 2 H), 6.68 (d, J = 9.0 Hz, 2 H), 3.89 (s,3 H), 3.08 (s, 3 H). MS (ESI) calcd for C₂₅H₂₂FN₃O₄S 479.1, found 502.1[M + Na]⁺. HPLC2: t_(R) 18.6 min, purity 96.9%.(3,4,5-trihydroxyphenyl)(2-(3,4,5- Yield: 66.1%. mp 294-296° C. ¹H NMRtrihydroxyphenyl)-1H-imidazol-4- (500 MHz, CD₃OD) δ 8.07 (s, 1 H), 7.07(s, 2 yl)methanone (13ea). H), 7.02 (s, 2 H). MS (ESI): calculated forC₁₆H₁₂N₂O₇, 344.1, found 345.0 [M + H]⁺, 342.9 [M − H]⁻. HPLC2: t_(R)3.62 min, purity 97.9%. (2-(4-chlorophenyl)-1H-imidazol-4-yl)(3,4,5-Yield: 79.3%; mp >300° C. ¹H NMR trihydroxyphenyl)methanone (13fa). (500MHz, CD₃OD) δ 8.02 (d, J = 8.5 Hz, 2 H), 7.77 (s, 1 H), 7.54 (d, J = 8.5Hz, 2 H), 7.14 (s, 2 H). MS (ESI): calculated for C₁₆H₁₁ClN₂O₄, 330.0,found 331.1 [M + Na]⁺, 328.9 [M − H]⁻. HPLC2: t_(R) 11.9 min, purity95.6%. (2-(3,4-dihydroxyphenyl)-1H-imidazol-4- Yield: 62.2%; mp >300° C.¹H NMR (500 MHz, yl)(3,4,5-trihydroxyphenyl)methanone (13ha). CD₃OD) δ8.11 (s, 1 H), 7.46 (d, J = 2.0 Hz, 1 H), 7.42 (dd, J = 8.5 Hz, 2.0 Hz,1 H), 7.10 (s, 2 H), 7.02 (d, J = 8.5 Hz, 1 H). MS (ESI): calculated forC₁₆H₁₂N₂O₆, 328.1, found 329.0 [M + H]⁺, 326.9 [M − H]⁻. HPLC2: t_(R)3.64 min, purity 97.9%. 2-(4-nitrophenyl)-4,5-dihydro-1H-imidazoleYield: 70.3%. ¹H NMR (500 MHz, CDCl₃) δ (14x). 8.30 (d, J = 9.0 Hz, 2H), 7.98 (d, J = 8.5 Hz, 2 H), 3.88-3.95 (m, 4 H). MS (ESI): calculatedfor C₉H₉N₃O₂, 191.10, found 191.9 [M + H]⁺, 189.7 [M − H]⁻.2-(4-fluorophenyl)-4,5-dihydro-1H-imidazole Yield: 60.2%. ¹H NMR (500MHz, CDCl₃) δ (14b). 7.80 (q, J = 7.0 Hz, 2 H), 7.11 (d, J = 10.0 Hz, 2H), 3.82 (br, 4 H). MS (ESI): calculated for C₉H₉FN₂, 164.10, found 165[M + H]⁺. 2-(4-methoxyphenyl)-4,5-dihydro-1H- Yield: 56.9%. ¹H NMR (500MHz, CDCl₃) δ imidazole (14c). 7.84 (d, J = 8.5 Hz, 2 H), 6.94 (d, J =9.0 Hz, 2 H), 3.87 (s, 3 H), 3.85 (br, 4 H). MS (ESI): calculated forC₁₀H₁₂N₂O, 176.10, found 177.0 [M + H]⁺.

Example 6 Synthesis of Selected Indolyl-Benzoyl-Imidazole Compounds

The synthesis of 15xaa is outlined in FIG. 12. This route was originallydesigned for the synthesis of 12xa, but the nonselectivity of thebenzoylation at the indole-2 and imidazole-4 positions resulted in theformation of 15xaa, which is a closely related but bulkier analog ofllxaa. The indole-5-carboxaldehyde 8x was protected by a phenylsulfonylgroup on the indole NH to afford intermediate 8xa. 8xa was reacted withglyoxal and ammonium hydroxide to generate the 2-aryl-imidazole 9xa.Protection of the imidazole NH with phenylsulfonyl gave the intermediate10xaa which was coupled with 3,4,5-trimethoxybenzoyl chloride to produce16xaa. Removal of the protecting group from 16xaa provided 15xaa.

Synthesis of 1-(Phenylsulfonyl)-1H-indole-5-carbaldehyde (8xa). To asolution of indole-3-carboxaldehyde (100 mmol) in ethanol (500 mL) atroom temperature was added potassium hydroxide (110 equiv), the mixturewas stirred until total solubilization. The ethanol was completelyremoved in vacuum and acetone (250 mL) added followed by benzenesulfonylchloride (110 equiv). The precipitate was filtered off and the filtratewas concentrated and recrystallized from methanol to give a white solid.Yield: 32.6% ¹H NMR (500 MHz, CDCl₃) δ 10.17 (s, 1H), 8.25-8.39 (m, 2H),7.97-8.09 (m, 3H), 7.69 (t, J=7.33 Hz, 1H), 7.59 (t, J=7.5 Hz, 2H),7.39-7.54 (m, 2H). MS (ESI) calcd for C₁₅H₁₁NO₃S 285.1. Found 286.0[M+H]⁺.

Synthesis of(5-(4-(3,4,5-Trimethoxybenzoyl)-1H-imidazol-2-yl)-1H-indol-2-yl)(3,4,5-trimethoxyphenyl)methanone(15xaa): To a solution of(1-(phenylsulfonyl)-2-(1-(phenylsulfonyl)-2-(3,4,5-trimethoxybenzoyl)-1H-imidazol-5-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(16xaa) (1 mmol) in ethanol (20 mL) was added sodium hydroxide (10equiv) and stirred overnight in darkness. The reaction mixture wasdiluted by 50 mL of water and extracted by ethyl acetate (250 mL). Theorganic layer was dried over magnesium sulfate and concentrated. Theresidue was purified by flash column chromatography (hexane:ethylacetate 3:1) or recrystallized from water and methanol to give a whitesolid. Yield: 30-95%.

5-(1H-Imidazol-2-yl)-1-(phenylsulfonyl)-1H-indole (9xa). Yield: 12.0%.¹H NMR (500 MHz, DMSO-d₆) δ 8.33 (d, J=2.9 Hz, 2H), 8.13 (d, J=7.8 Hz,2H), 7.98-8.04 (m, 1H), 7.62-7.67 (m, 1H), 7.55 (d, J=7.82 Hz, 2H),7.22-7.34 (m, 4H). MS (ESI) calcd for C₁₇H₁₃N₃O₂S 323.1. Found 324.0[M+H]⁺.

1-(Phenylsulfonyl)-5-(1-(phenylsulfonyl)-1H-imidazol-2-yl)-1H-indole(10xaa). Yield: 23.6%. ¹H NMR (500 MHz, CDCl₃) δ 8.01 (d, J=8.5 Hz, 1H),7.95 (d, J=7.5 Hz, 2H), 7.73 (d, J=1.0 Hz, 1H), 7.70 (d, J=4.0 Hz, 1H),7.63-7.66 (m, 2 μl), 7.52-7.56 (m, 3H), 7.31-7.34 (m, 3H), 7.22 (t,J=8.5 Hz, 2H), 7.17 (s, 1H), 6.14 (d, J=3.5 Hz, 1H). MS (ESI) calcd forC₂₃H₁₇N₃O₄S₂ 463.1. Found 464.0 [M+H]⁺.

(1-(Phenylsulfonyl)-2-(1-(phenylsulfonyl)-2-(3,4,5-trimethoxybenzoyl)-1H-indol-5-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(16xaa). Yield: 15.9%. ¹H NMR (500 MHz, CDCl₃) δ 8.18-8.25 (m, 3H), 8.04(d, J=8.1 Hz, 2H), 7.70-7.78 (m, 2 H), 7.61-7.69 (m, 3H), 7.55 (t, J=7.7Hz, 3H), 7.50 (s, 1H), 7.38 (s, 2H), 7.34 (s, 2H), 6.94 (s, 1H),3.99-4.06 (m, 12H), 3.94-3.99 (m, 6H). MS (ESI) calcd for C₄₃H₃₇N₃O₁₂S₂851.2. Found 852.1 [M+H]⁺.

(5-(4-(3,4,5-Trimethoxybenzoyl)-1H-imidazol-2-yl)-1H-indol-2-yl)(3,4,5-trimethoxyphenyl)methanone(15xaa). Yield: 45.9%; mp 239-241° C. ¹H NMR (500 MHz, CDCl₃) δ 10.45(s, 1H), 9.44 (s, 1H), 8.41 (s, 1H), 8.04 (d, J=8.5 Hz, 1H), 7.86 (s,1H), 7.61 (d, J=8.5 Hz, 1H), 7.29 (s, 2H), 7.26 (s, 2H), 3.99 (s, 3H),3.95-3.97 (m, 15H). MS (ESI) calcd for C₃₁H₂₉N₃O₈ 571.2. Found 572.2[M+H]⁺. HPLC2: t_(R) 4.09 min, purity 96.3%.

Example 7 Synthesis of(2-(1H-INDOL-3-YL)-1H-IMIDAZOL-4-YL)(3,4,5-TRIMETHOXYPHENYL)METHANONE(17YA) (FIG. 13)

Synthesis of 1-(phenylsulfonyl)-1H-indole-3-carboxaldehyde (8ya): To asolution of indole 3-carboxaldehyde (8y) (100 mmol) in ethanol (500 mL)at RT was added potassium hydroxide (1.1 equiv). The mixture was stirreduntil total solubilization. The ethanol was completely removed in vacuumand the residual was dissolved in acetone (250 mL) followed by addingbenzenesulfonyl chloride (1.1 equiv, 110 mmol). The reaction mixture wasstirred for half hour. The precipitate was filtered off and the filtratewas concentrated and recrystallized from methanol to give a white solid.Yield: 33%. ¹H NMR (500 MHz, CDCl₃) δ 10.17 (s, 1H), 8.25-8.39 (m, 2H),7.97-8.09 (m, 3H), 7.69 (t, J=7.33 Hz, 1H), 7.59 (t, J=7.5 Hz, 2H),7.39-7.54 (m, 2H). MS (ESI) calcd for C₁₅H₁₁NO₃S 285.1. Found 286.0[M+H]⁺.

Synthesis of 3-(1H-imidazol-2-yl)-1-(phenylsulfonyl)-1H-indole (9ya): Toa solution of 1-(phenylsulfonyl)-1H-indole-3-carboxaldehyde (8ya) (100mmol) in ethanol (400 mL) at 0° C. was added a solution of 40%oxalaldehyde (glyoxal) in water (1.1 equiv, 110 mmol) and a solution of29% ammonium hydroxide in water (10 equiv, 1000 mmol).² After stirringfor 2-3 days at RT, the reaction mixture was quenched by water andextracted by dichloromethane. The organic layer was removed by vacuumand the residue was subjected to flash column chromatography withhexane/ethyl acetate (4:1-2:1) as eluent to yield the titled compound asa yellow powder. Yield: 12%. ¹H NMR (500 MHz, DMSO-d₆) δ 8.33 (d, J=2.9Hz, 2H), 8.13 (d, J=7.8 Hz, 2H), 7.98-8.04 (m, 1H), 7.62-7.67 (m, 1H),7.55 (d, J=7.82 Hz, 2H), 7.22-7.34 (m, 4H). MS (ESI) calcd forC₁₇H₁₃N₃O₂S 323.1. Found 324.0 [M+H]⁺.

Synthesis of1-(phenylsulfonyl)-3-(1-(phenylsulfonyl)-1H-imidazol-2-yl)-1H-indole(10ya): To a solution of3-(1H-imidazol-2-yl)-1-(phenylsulfonyl)-1H-indole (9ya) (20 mmol) inanhydrous THF (300 mL) at 0° C. was added sodium hydride (60% dispersionin mineral oil, 1.2 equiv, 24 mmol) and stirred for 20 min.²Benzenesulfonyl chloride (1.2 equiv, 24 mmol) was added and the reactionmixture was stirred overnight. After dilution by 200 mL of saturatedNaHCO₃ solution (aqueous), the reaction mixture was extracted by ethylacetate (600 mL). The organic layer was dried over magnesium sulfate andconcentrated. The residue was purified by flash column chromatography(hexane:ethyl acetate 5:1) to give a white solid. Yield: 40%. ¹H NMR(CDCl₃, 300 MHz) δ 8.02-8.08 (m, 4H), 7.72 (d, J=1.5 Hz, 1H), 7.35-7.60(m, 8H), 7.23 (d, J=1.5 Hz, 1H), 7.10-7.16 (m, 3H). MS (ESI) calcd forC₂₃H₁₇N₃O₄S₂ 463.1. Found 486.0 [M+Na]⁺.

Synthesis of(1-(phenylsulfonyl)-2-(1-(phenylsulfonyl)-1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(17yaa): To a solution of1-(phenylsulfonyl)-3-(1-(phenylsulfonyl)-1H-imidazol-2-yl)-1H-indole(10ya) (5.0 mmol) in anhydrous THF (100 mL) at −78° C. was added 1.7 Mtert-butyllithium in pentane (1.2 equiv, 6.0 mmol) and stirred for 10min. A solution of 3,4,5-trimethoxybenzoyl chloride (1.2 equiv, 6.0mmol) in THF was added at −78° C. and stirred overnight.² The reactionmixture was quenched with 100 mL of saturated NaHCO₃ solution (aqueous)and extracted by ethyl acetate (300 mL). The organic layer was driedover magnesium sulfate and concentrated. The residue was purified byflash column chromatography (hexane:ethyl acetate 3:1) to give a whitesolid. Yield: 30%. ¹H NMR (500 MHz, CDCl₃) δ 8.09 (d, J=10 Hz, 1H), 8.04(d, J=10 Hz, 2H), 7.91 (s, 1H), 7.76 (d, J=5 Hz, 2H), 7.65 (t, J=10 Hz,1H), 7.55-7.58 (m, 5 H), 7.40 (s, 2H), 7.33-7.36 (m, 3H), 7.25 (t, J=10Hz, 1H), 4.05 (s, 3H), 4.03 (s, 6H). MS (ESI) calcd for C₃₃H₂₇N₃O₈657.0. Found 680.1 [M+Na]⁺.

Synthesis of(2-(1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(17ya): To a solution of(1-(phenylsulfonyl)-2-(1-(phenylsulfonyl)-1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(17yaa) (1 mmol) in ethanol (40 mL) and water (4 mL) was added sodiumhydroxide (10 equiv, 10 mmol) and stirred overnight under refluxingcondition in darkness. The reaction mixture was diluted by 50 mL ofwater and extracted by ethyl acetate (200 mL). The organic layer wasdried over magnesium sulfate and concentrated. The residue was purifiedby flash column chromatography (hexane:ethyl acetate 1:1) to give ayellow solid. Yield: 60%. ¹H NMR (500 MHz, CD₃OD) δ 8.31 (d, J=6.5 Hz,1H), 7.99 (s, 1H), 7.90 (s, 1H), 7.48-7.52 (m, 3H), 7.24-7.28 (m, 2H),4.00 (s, 6H), 3.93 (s, 3H). MS (ESI) calcd for C₂₁H₁₉N₃O₄ 377.1. Found400.1 [M+Na]⁺. Mp 208-210° C.

Example 8 Synthesis of(2-(1H-indol-5-ylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(compound 55) (FIG. 15).

A mixture of 5-nitro-1H-indole (11 g, 67.9 mmol) and Pd/C (5%; 1g),dissolved in ethanol (50 mL), was hydrogenated for 3 h at 40 psi. Thereaction mixture was filtered and the excess of ethanol was evaporatedunder reduced pressure. Solid product was recrystallized from hexane toobtain the pure compound 5-aminoindole (55-1). Yield: 92.5%. ¹H NMR (500MHz, CDCl₃): δ 7.96 (br, 1H), 7.20 (d, 1H), 7.13 (s, 1H), 6.95 (s, 1H),6.67 (dd, 1H), 6.37 (s, 1H), 3.50 (s, 2H). MS (ESI) m/z 133.0 (M+H)⁺.

A solution of 5-aminoindole (8 g, 60.6 mmol) in acetone (150 mL) wasreacted with benzoylisothiocyanate (9.88 g, 60. mmol) at RT for about 4h. The resulting solid was filtered and treated with 2 N NaOH in THF(120 mL). The mixture was refluxed for about 6 h and allowed to warm toRT. The solvent was evaporated off under vacuum. The residue was dilutedwith water (20 mL) and neutralized to pH 7 with 1N HCl. The resultingsolid was filtered and dried under vacuum to afford 5-indolylthiourea(55-2). 5-Indolyl thiourea (0.01 mol) and ethyl bromopyruvate (0.011mol) were dissolved in 3 mL ethanol and held at reflux for 2 h. Thereaction was cooled, the crystalline ethyl2-(1H-indol-5-ylamino)thiazole-4-carboxylate (55-3) was collected byfiltration and washed with ethanol. Refluxing the mixture of ethylesters with the NaOH-ethanol solution gave2-(1H-indol-5-ylamino)thiazole-4-carboxylic acid (55-4) which was useddirectly in next steps. To a mixture of the crude acid (2.5 mmol), EDCI(2.9 mmol), HOBt (2.6 mmol) and NMM (5.3 mmol) in CH₂Cl₂ (30 mL) wasadded HNCH₃OCH₃HCl salt (2.6 mmol) and stirring continued at RT forovernight. The reaction mixture was diluted with CH₂Cl₂ (20 mL) andsequentially washed with water, satd. NaHCO₃, brine and dried overMgSO₄. The solvent was removed under reduced pressure to yield a crudeproduct, which was purified by column chromatography to obtain purecompound 2-(1H-indol-5-ylamino)-N-methoxy-N-methylthiazole-4-carboxamide(55-5) (45.6% yield for overall 5 steps). At −78° C., to a solution of5-bromo-1,2,3-trimethoxybenzene (1.235 g, 5.0 mmol) in 30 mL THF wascharged n-BuLi in hexane (2.5 N, 2.4 mL, 6 mmol) under Ar₂ protectionand stirred for 10 min Weinreb amide (1 mmol) in 10 ml, THF was added tolithium reagent and allowed to stir at RT for 2 h. The reaction mixturewas quenched with satd. NH₄Cl, extracted with ethyl ether, dried withMgSO₄. The solvent was removed under reduced pressure to yield a crudeproduct, which was purified by column chromatography to obtain purecompound 55 (51.7% yield). ¹H NMR (300 MHz, CDCl₃) δ 8.29 (br, 1H), 7.68(d, 1H), 7.46 (s, 2H), 7.39 (s, 1H), 7.36 (s, 1H), 7.28-7.26 (m, 1H),7.15-7.12 (m, 1H), 6.55 (m, 1H), 3.93 (s, 3H), 3.89 (s, 6H). MS (ESI)m/z 432.1 (M+Na)⁺, 408.0 (M−H)⁻.

Example 9 Synthesis of Quinoline- and Isoquinoline-Aryl Compounds (FIG.16).

A series of compounds were prepared by Suzuki coupling of7-bromo-1-chloroisoquinoline with various arylboronic acids.

Synthesis of 1-Chloro-7-(1H-indol-5-yl)-isoquinoline (6d) (FIG. 16C)

A mixture of 7-bromo-1-chloroisoquinoline (0.50 g, 2.1 mmol),5-indoleboronic acid (0.40 g, 2.5 mmol),tetrakis(triphenylphosphene)palladium (0.035 g, 0.08 mmol), potassiumcarbonate (2.1 mL, 2 M, 4.1 mmol), N,N-dimethylformamide (11 mL) wasstirred while purging the headspace with argon for 30 min. The mixturewas then brought to reflux for 16 h before being allowed to cool to RT.The mixture was filtered through a bed of silica gel, diluted with water(50 mL), and extracted with ethyl acetate (50 mL). The organic layer wasseparated and washed with NaOH (2×20 mL, 10% aq.), water (5×30 mL, untilrefractive changes were no longer seen at the organic-aqueousinterface), and ammonium chloride (20 mL, sat.). The organic layer wasthen adsorbed onto silica gel and flash-chromatographed (ethylacetate/hexanes) to afford 0.14 g (25%) of a yellow solid. MS (ESI):calculated for C₁₇H₁₁ClN₂, 278.1. Found 301.0 [M+Na]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 6.56-6.58 (m, 1H), 7.44 (t, J=2.77 Hz, 1H), 7.57-7.59 (m,2H), 7.93 (m, 1H), 8.04 (s, 1 H), 8.13-8.20 (m, 1H), 8.27-8.31 (m, 2H),8.43 (m, 1H), 11.25 (brs, 1H).

1,7-Bis-(1H-indol-5-yl)-isoquinoline (6b) (FIG. 16E)

A mixture of 7-bromo-1-chloroisoquinoline (0.20 g, 2.1 mmol),5-indoleboronic acid (0.80 g, 5.0 mmol),tetrakis(triphenylphosphene)palladium (0.19 g, 0.16 mmol), potassiumcarbonate (2.1 mL, 2 M, 4.1 mmol), N,N-dimethylformamide (11 mL) wasstirred while purging the headspace with argon for 30 min. The mixturewas then brought to reflux for 16 h before being allowed to cool to RT.The mixture was filtered through a bed of silica gel, diluted with water(50 mL), and extracted with ethyl acetate (50 mL). The organic layer wasseparated and washed with NaOH (2×20 mL, 10% aq.), water (5×30 mL, untilrefractive changes were no longer seen at the organic-aqueousinterface), and ammonium chloride (20 mL, sat.). The organic layer wasthen adsorbed onto silica gel and flash-chromatographed (ethylacetate/hexanes) to afford 0.29 g (39%) of a yellow solid. MS (ESI):calculated for C₂₅H₁₇N₃, 359.1. Found 360.2 [M+H]⁺ 382.1 [M+Na]⁺, and358.0 [M−H]⁻. ¹H NMR (500 MHz, DMSO-d₆) δ 6.46-6.50 (m, 1H) 6.52-6.59(m, 1H) 7.34-7.36 (m, 1H) 7.36-7.41 (m, 2H) 7.42-7.52 (m, 3H) 7.58 (d,J=8.30 Hz, 1H) 7.81 (dd, J=5.49, 5.00 Hz, 2H) 7.92 (s, 1H) 8.08-8.17 (m,2H) 8.33 (s, 1H) 8.54 (d, J=5.61 Hz, 1H) 11.18 (br. s., 1 H) 11.30 (br.s., 1H) ppm.

1-(4-Fluoro-phenyl)-7-(1H-indol-5-yl)-isoquinoline (6c) (FIG. 16D)

A mixture of 6d (0.20 g, 0.72 mmol), 4-fluorophenylboronic acid (0.12 g,0.86 mmol), tetrakis(triphenylphosphene)palladium (0.033 g, 0.03 mmol),potassium carbonate (0.72 mL, 2-M, 1.4 mmol), N,N-dimethylformamide (22mL) was stirred while purging the headspace with argon for 30 min. Themixture was then brought to reflux for 16 h before being allowed to coolto RT. The mixture was filtered through a bed of silica gel, dilutedwith water (50 mL), and extracted with ethyl acetate (50 mL). Theorganic layer was separated and washed with NaOH (2×20 mL, 10% aq.),water (5×30 mL, until refractive changes were no longer seen at theorganic-aqueous interface), and ammonium chloride (20 mL, sat.). Theorganic layer was then adsorbed onto silica gel andflash-chromatographed (ethyl acetate/hexanes) to afford 0.038 g (16%) ofa yellow solid. MS (ESI): calculated for C₂₃H₁₅FN₂, 338.12. Found 339.2[M+H]⁺ and 361.2 [M+Na]. ¹H NMR (300 MHz, DMSO-d₆) δ 6.47-6.55 (m, 1H),6.80 (d, J=9.16 Hz, 2H), 7.38-7.45 (m, 2H), 7.47-7.62 (m, 3 H), 7.72 (d,J=8.85 Hz, 2H), 7.79-7.96 (m, 3H), 11.18 (br. s., 1H).

1,7-Bis-(4-fluoro-phenyl)-isoquinoline (40) (FIG. 16A)

MS (ESI): calculated for C₂₁H₁₃F₂N, 317.10. Found 318.1 [M+H]⁺, 340.1[M+Na]⁺, and 315.9 [M−H]⁻. ¹H NMR (500 MHz, DMSO-d₆) δ 7.31 (br. s., 1H)7.31-7.37 (m, 2H) 7.39 (br. s., 1H) 7.41 (t, J=8.54 Hz, 2H) 7.72-7.77(m, 2H) 7.78-7.84 (m, 2H) 7.89 (br. s., 1H) 7.90-7.99 (m, 1H) 8.09-8.19(m, 3H) 8.59 (br. s., 1H) 8.60-8.65 (m, 1 H) ppm.

Synthesis of7-Bromo-1-(4-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline (43)and1-(4-Fluoro-benzenesulfonyl)-7-(1H-indol-5-yl)-1,2,3,4-tetrahydroquinoline(41). (FIG. 16B).

7-Bromo-1,2,3,4-tetrahydroquinoline (0.60 g, 2.8 mmol) was stirred with4-fluorophenylsulphonyl chloride (1.65 g, 8.49 mmol) in pyridine (5 mL)at 80° C. for 3 h. The mixture was cooled, concentrated, and the residuewas chromatographed (EtOAc/Hexanes on SiO₂) to give 845 mg of a brownsolid (81%) of compound 43. C₁₅H₁₃BrFNO₂S 368.98. found 394.0 [M+Na] and367.8 [M−H]⁻. ¹H NMR (500 MHz, CDCl₃-d) δ 1.58-1.67 (m, 2 H) 2.41 (t,J=6.71 Hz, 2H) 3.72-3.82 (m, 2H) 6.89 (d, J=8.30 Hz, 1H) 7.08-7.17 (m,2H) 7.18-7.24 (m, 1H) 7.59-7.68 (m, 2H) 7.92-8.01 (m, 1H) ppm.

43 (0.46 g, 1.3 mmol), 5-indoleboronic acid (0.26 g, 1.6 mmol),tetrakis(triphenylphosphene)palladium (0.031 g, 0.03 mmol), potassiumcarbonate (1.35 mL, 2-M, 2.7 mmol), and N,N-dimethylformamide (135 mL)were stirred while purging the headspace with argon for 30 min. Themixture was then brought to reflux for 16 h before being allowed to coolto RT. The mixture was filtered through a bed of silica gel, dilutedwith water (50 mL), and extracted with ethyl acetate (50 mL). Theorganic layer was separated and washed with NaOH (2×20 mL, 10% aq.),water (5×30 mL, until refractive changes were no longer seen at theorganic-aqueous interface), and ammonium chloride (20 mL, sat.). Theorganic layer was then adsorbed onto silica gel andflash-chromatographed (ethyl acetate/hexanes) to afford 0.38 g (77%) ofa white crystalline solid of compound 41. MS (ESI): calculated forC₂₃H₁₉FN₂O₂S, 406.12. Found 404.9 [M−H]⁻ and 429.1 [M+Na]⁺. NMR (500MHz, DMSO-d₆) δ 1.56-1.66 (m, 2H) 2.48 (t, J=6.59 Hz, 2H) 3.76-3.86 (m,2 H) 6.46-6.56 (m, 1H) 7.14 (m, J=7.81 Hz, 1H) 7.33-7.37 (m, 1H)7.38-7.45 (m, 4H) 7.49 (m, J=8.54 Hz, 1H) 7.66-7.74 (m, 2H) 7.74-7.81(m, 1H) 7.85-7.94 (m, 1 μl) 11.17 (br. s., 1H) ppm.

7-Bromo-2-(4-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinoline(42) (FIG. 16B)

Yield 23%. C₁₅H₁₃BrFNO₂S, 369.0. Found 392.0 [M+Na] and 367.7 [M−H]⁻. ¹HNMR (500 MHz, DMSO-d₆) δ 2.75-2.82 (m, 2H) 3.32 (t, J=6.10 Hz, 2H) 4.24(s, 2 H) 7.07 (d, J=8.30 Hz, 1H) 7.29-7.37 (m, 1H) 7.37-7.43 (m, 1H)7.47 (t, J=8.79 Hz, 2H) 7.87-7.93 (m, 2H) ppm.

2-(4-Fluoro-benzenesulfonyl)-7-(1H-indol-5-yl)-1,2,3,4-tetrahydro-isoquinoline(44)

Yield 77%. ¹H NMR (500 MHz, DMSO-d₆) δ 2.84-2.91 (m, 2H) 3.35 (t, J=5.98Hz, 2H) 4.30 (s, 2H) 6.44-6.48 (m, 1H) 7.17 (d, J=7.81 Hz, 1H) 7.32-7.40(m, 2 H) 7.41-7.51 (m, 3H) 7.75-7.79 (m, 1H) 7.89-7.96 (m, 1H) 11.13(br. s., 1H) ppm.

Example 10 Water Solubility of Aryl-Benzoyl-Imidazole (ABI) Compounds(FIG. 17)

Determination of water solubility. To determine water solubility, 1 mgof each compound was suspended in 1 mL water and shaken for 48 h at roomtemperature (RT). The suspension was centrifuged at 10,000 rpm for 10min and filtered on 0.22 m filter. Concentrations of each compound weremeasured by LC-MS, consisting of an HP S1100 HPLC instrument (Agilent,Foster ceity, CA) and a Bruker ESQUIRE MS detector with electrospray/iontrap instrument in positive ion mode (Bruker, Fremont, Calif.). ForHPLC, a reverse phase Nova-pak C18 column (150 mmx 3.9 mm, Waters,Milford, Mass.) was used. The mobile phase was composed of 20:80 v/vwater/acetonitrile. For MASS, the peak was extracted at 382 m/z (forimidazole compounds) and 399 m/z (for thiazole compounds) respectively.The concentration of each compound was calculated by MS peak areaaccording to the following calibration equation: y=1.3295x+114.24(R²=1.00). To make the standard curve (FIG. 17) from which the equationwas derived, 50, 100 μL of each 100 μg/mL, 10 μg/mL of ABI compound12ga, and its corresponding thiazole analog, as well as CA-4 (see FIG.19 for structure) in acetonitrile, were injected into HPLC and monitoredby mass spectroscopy. The amount (ng) in each injection was plottedagain its relative mass peak area to generate the standard curve in FIG.17.

The HPLC retention times of ABI compound 12ga (1.5 min) was compared toits corresponding thiazole analog (2.2 min) using 80/20 methanol/watermobile phase at 1 mL/min flow rate and a reversed phase column,indicating that the imidazole derivative was more hydrophilic than itscorresponding thiazole analog. The calculated logP values for ABIcompound 12ga and the corresponding thiazole analog were approximately2.9 and 4.4, respectively. The water solubility of compound 12ga was 13μg/mL, or about 200 times greater than its thiazole counterpart (72ng/mL).

Example 11 Biological Evaluation of Compounds of this Invention Example11A In Vitro Cell Growth Inhibitions

Cell Culture and Cytotoxicity Assay of Prostate Cancer and Melanoma. Allcell lines were obtained from ATCC (American Type Culture Collection,Manassas, Va., USA), while cell culture supplies were purchased fromCellgro Mediatech (Herndon, Va., USA). We examined the antiproliferativeactivity of our anti-tubulin compounds in four human prostate cancercell lines (LNCaP, DU 145, PC-3, and PPC-1) and two human melanoma celllines (A375 and WM-164). Human ovarian cell line OVCAR-8 and itsresistant cell line that over-expresses P-gp (NCI/ADR-RES) were used asMDR models. Both ovarian cell lines were obtained from National CancerInstitutes (NCI). All cell lines were tested and authenticated by eitherATCC or NCI. All prostate cancer and ovarian cancer cell lines werecultured in RPMI 1640, supplemented with 10% fetal bovine serum (FBS).

Melanoma cells were cultured in DMEM, supplemented with 5% FBS, 1%antibiotic/antimycotic mixture (Sigma-Aldrich, Inc., St. Louis, Mo.,USA) and bovine insulin (5 μg/mL; Sigma-Aldrich). The cytotoxicpotential of the anti-tubulin compounds was evaluated using thesulforhodamine B (SRB) assay after 96 h of treatment.

All of the reported compounds were first evaluated for cytotoxicity inthe mouse melanoma cell line B16-F1, human melanoma cell lines (A375 andWM-164) and prostate cancer cell lines (DU145, PC-3, LNCaP, PPC-1).Compound 1h and ABT-751 (E7010; Abbott Laboratories/Eisai Co Ltd), whichhas entered phase II clinical studies in treating patients withdifferent cancers, were included in the assays as examples ofcolchicine-site binding agents. IC₅₀ values for cell growth inhibitionare shown in Tables 1, 2 and 3.

Results:

TABLE 1 SAR of B ring Optimizing Compounds IC₅₀ ± SEM(nM)

B ring B16-F1 A375 DU 145 PC-3 LNCaP PPC-1 la 1, 3-phenyl 500 ± 200 87 ±15 178 81 234 85 1b 4,6-pyrimidine >30000 >30000 6900 8300 7000 3700 1c2,6-pyridine 39 ± 12 30 ± 14 33 ± 3  32 ± 2  27 ± 2  25 ± 1  1d2,5-furan 151 ± 24  27 ± 8 35 21 23 20 1e 2,5-thiazole 12500 ± 520013600 ± 3800  >10000 >10000 >10000 >10000 1f 2,4-thiophene 72 ± 15 15 ±6  26 12 17 15 1g1,4-piperidine >30000 >30000 >20000 >20000 >20000 >20000 1h 2,4-thiazole55 ± 5  28 ± 5 71 ± 4  21 ± 1  28 ± 4  43 ± 5  1i3,5-isoxazole >30000 >30000 >10000 >10000 >10000 >10000 36a 2,4-oxazole600 ± 200 300 ± 100 292 294 310 324 35a 2,4-oxazoline 6500 ± 800  500 ±100 1200 ± 100  1200 ± 100  1200 ± 100  1100 ± 100 

TABLE 2 SAR of Carbonyl Linker Optimizing Compounds IC₅₀ ± SEM (nM)

X linker B16-F1 A375 WM-164 DU 145 PC-3 LNCaP PPC-1 1h C═O 55 ± 5  28 ±5  64 ± 4  71 ± 4  21 ± 1  28 ± 4  43 ± 5  2a C═CMe₂ 3800 ± 1300 1900 ±800  3700 ± 1200 2650 2470 1390 2040 2b CHOH >30000 >30000ND >10000 >10000 >10000 >10000 2c-trans syn-C═C—CN 5400 ± 2100 4600 ±1500 4900 ± 1300 2280  890  580  900 2c-cis anti-C═C—CN 1200 ± 300  1200± 400  1000 ± 200  ~10000 ~10000 1990 ~10000 2d-cis syn- C═N—NH₂ 2000 ±800  900 ± 300 ND 1210 1120 1800  872 2d-trans anti- C═N—NH₂ 1800 ± 700 600 ± 200 ND 1210 1040 1300  966 2e-cis syn- C═N—OH 300 ± 100 200 ± 100 ND* 102  120  189  160 2e-trans anti- C═N—OH 11400 ± 2100  7800 ± 1200ND >10000 >10000 >10000 >10000 2f-cis syn- C═N—OMe  3800 ± 16000 2900 ±1200 3400 ± 1800 >10000 >10000 >10000 >10000 2f-transanti-C═N—OMe >10000 >10000 >10000 >10000 >10000 >10000 >10000 2gCONH >30000 >30000 ND >10000 >10000 >10000 >10000 2h NHCO >30000 >30000ND >10000 >10000 >10000 >10000 2i bond(none) >10000 >10000 >10000 >10000 >10000 >10000 >10000 2j C═N—CN 60 ±21 28 ± 12 27 ± 13 42 ± 2  27 ± 1  23 ± 2  20 ± 1  3a cis-C═C 11000 ±2800  46500 ± 23300 10600 ± 5800  >10000 >10000 >10000 >10000 3btrans-C═C 32800 ± 13000 >10000 30800 ± 12000 >10000 >10000 >10000 >100004a S 2400 ± 900  1600 ± 400  2000 ± 1200 >10000 >10000 2300 ± 200  2300± 100  4b SO₂ >10000 >10000 >10000 >10000 >10000 >10000 >10000 4cSO >10000 >10000 >10000 >10000 >10000 >10000 >10000 4dSO₂NH₂ >10000 >10000 >10000 >10000 >10000 >10000 >10000 *ND = Notdetermined

TABLE 3 Antiproliferative Activity of Modified Compounds with ImprovedAqueous IC₅₀ ± SEM (nM)

A part B16-F1 A375 DU 145 PC-3 LNCaP PPC-1 58a 4-OTBDMSPh 500 ± 200 700± 300 434 ± 30  183 ± 24  549 246 ± 8  21 4-OHPh 110 100  116  87  103 76 62a 2-indolyl 43 ± 21 19 ± 9   32  24  28  28 66a 5-indolyl 25 ± 138 ± 1  13   7  10   8 68a 4-BocNHCH₂Ph 2900 ± 400  7900 ± 500  4400 31002600 2700 2r 4-NH₂CH₂Ph 38 ± 11 41 ± 13  25  80  13  34 2s4-NHMeCH₂Ph >10000 >10000 ~10000 >10000 114 ± 80  ~1000 2u4-NMe₂CH₂Ph >10000 >10000 >10000 >10000 1025 ± 200  >10000 5a PhNH 65 ±12 45 ± 8  70 ± 4  57 ± 3  51 ± 1  54 ± 1  5Hb 4-CH₃PhNH  ND* ND 35 ± 1 38 ± 2  35 ± 1  36 ± 1  5c 4-FPhNH ND ND 63 ± 1  43 ± 1  41 ± 1  37 ± 1 1h Ph 55 ± 5 28 ± 5  71 ± 4  21 ± 1  28 ± 4  43 ± 5  ABT-751 2127 ± 351 1111 ± 108  839 ± 719 786 ± 89  658 ± 117 701 ± 307 *ND = Not determined

SAR of alternative “B” ring molecules. The first series was targeted toalternatives to the thiazole “B” ring. Accordingly, a series ofheterocyclic “B” rings were examined. As shown in Table 1, thesuccessful replacements of the thiazole were pyridine 1c, furan 1d andthiophene 1f. The IC₅₀s (12 nM˜35 nM against prostate cancer cells) areclose to the thiazole compound 1h. Introducing phenyl (1a), oxazoline(35a), and oxazole (36a) maintained activity in the hundreds ofnanomolar range. But introducing of pyrimidine (1b, IC₅₀: 3.7˜8.3 μM), areversed 2,5-thiazole and 3,5-isoxazole (1e and 1i, IC₅₀: >10 μM) causedobvious losses of potency. Modification of “B” ring to the saturatedring of piperidine (1 g) also totally abolished activity (IC₅₀>20 μM).

SAR of Alternative Linkers. In vitro hepatic metabolic stability studiesrevealed that the carbonyl linker between “B” and “C” rings in SMARTcompounds caused short half lives (5-17 min) primarily due to carbonylreduction. For the sake of blocking this ketone reduction to theinactive hydroxyl linker compound 2b, the carbonyl linker in the secondseries of compounds was modified (Table 2). The carbonyl linker wasreplaced with double bonds (2a, 3a and 3b), amides (2g, 2h), oximes(2e-cis,trans and 2f-cis,trans), hydrazide (2d-cis, 2d-trans),acrylonitriles (2c-trans, 2c-cis), cyanoimine (2j), sulfonyl amide (4d),sulfur ether (4a), sulfonyl and sulfinyl compounds (4b, 4c). A directlink compound 21 without any linker between “B” and “C” rings was alsoprepared. Among these linker modifications, only cyanoimine linkage (2j)showed promising potential (20˜60 nM) compared with carbonyl compound1h, but an in vitro metabolism study showed that the half life of 2j inhuman liver microsome was less than 5 min. It is suggested that althoughthe ketone reduction is blocked, it might introduce a new metabolicliability in compound 2j. The isomer pairs of compounds containingdouble bonds, oximes and hydrazides were separated. Compound 3a wasdesigned to mimic the structure of CA-4, (FIG. 19) which contain acis-C═C between two aryl rings, unfortunately 3a and other isomer pairslost activity after replacing the C═O linker. One interesting phenomenonis syn-isomer of 2e-cis (0.1˜0.3 μM) showed 10 fold more activity thanits anti-isomer 2e-trans (>10 μM). The half life of 2e-cis in humanliver microsome is extended to 35 min, while half lives of compounds 2dcan be prolonged to 55 min. But decreased activity (˜1 μM) of 2d alsoreduced their potency.

Example 11B Aqueous Solubility of Compounds of the Invention

The solubility of drugs was determined by Multiscreen Solubility FilterPlate (Millipore Corporate, Billerica, Mass.) coupled with LC-MS/MS.Briefly, 198 μL of phosphate buffered saline (PBS) buffer (pH 7.4) wasloaded into 96-well plate, and 2 μL of 10 mM test compounds (in DMSO)was dispensed and mixed with gentle shaking (200-300 rpm) for 1.5 h atRT (N=3). The plate was centrifuged at 800 g for 5 min, and the filtratewas used to determine its concentration and solubility of test compoundby LC-MS/MS as described below.

Introducing polar and ionizable groups into the anti-tubulin agents. Onemajor limitation of the SMART agents is low aqueous solubility.Surfactants such as Tween 80, were used to study in vivo SMART behavior,accordingly favorable results were obtained. But these surfactants arebiologically active and are responsible for many side effects. Inaddition, it was thought that low aqueous solubility of 1 h resulted inlow oral bioavailability (3.3%, Table 4). In the third series ofcompounds, the aqueous solubility was successfully increased withoutimpacting the potency by introducing polar groups like hydroxyl andindolyls. In addition, ionizable groups like amino and alkylamino groupswere also introduced into “A” ring para-position. As shown in FIG. 5 andTable 3, introducing indolyl groups to the “A” ring especially 5-indolyl(66a, 7˜25 nM) increased the potency compared with the 4-OH compound 21(76-116 nM). Aminomethyl —CH₂NH₂ at the “A” ring para position alsomaintained potency (2r, 13-80 nM), but p-NHMe (2s) or p-NMe₂ (2u)abrogated activity. As shown in FIG. 18, analytical measurement toestimate aqueous solubility showed that indolyl compound 66a increasedsolubility in PBS from 1.1 μg/mL (compound 1h) to 3.8 μg/mL. Aminomethylcompound 2r was converted to the HCl salt, which increased solubilityover 35-fold (>35 μg/mL). Although compound 2r showed satisfactoryaqueous solubility, the pharmacokinetic studies showed this compoundstill had very poor bioavailability (F %=0.2%). It was thought thatcompound 2r was ionized in the stomach, and therefore not absorbed intothe circulation system.

Example 11 C: Pharmacokinetic Studies

Pharmacokinetic Study. Female Sprague-Dawley rats (n=3 or 4; 254±4g)were purchased from Harlan Inc. (Indianapolis, Ind.). Rat thoracicjugular vein catheters were purchased from Braintree Scientific Inc.(Braintree, Mass.). On arrival at the animal facility, the animals wereacclimated for 3 days in a temperature-controlled room (20-22° C.) witha 12-h light/dark cycle before any treatment. Compound 1h wasadministered intravenously (i.v.) into the jugular vein catheters at adose of 2.5 mg/kg (in DMSO/PEG300, 2/8), whereas 5Ha and 5Hc were dosedat 5 mg/kg (in DMSO/PEG300, 1/9). An equal volume of heparinized salinewas injected to replace the removed blood, and blood samples (250 μL)were collected via the jugular vein catheters at 10, 20, 30 min, and 1,2, 4, 8, 12, 24 hr. Compounds 1h, 5Ha and 5Hc were given (p.o.) by oralgavage at 10 mg/kg (in Tween80/DMSO/H₂O, 2/1/7). All blood samples (250μL) after oral administration were collected via the jugular veincatheters at 30, 60, 90 min, 120 min, 150 min, 180 min, 210 min, 240min, and 8, 12, 24 h. Heparinized syringes and vials were prepared priorto blood collection. Plasma samples were prepared by centrifuging theblood samples at 8,000 g for 5 min. All plasma samples were storedimmediately at −80° C. until analyzed.

Analytes were extracted from 100 μL of plasma with 200 μL ofacetonitrile containing 200 nM the internal standard((3,5-dimethoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone). The sampleswere thoroughly mixed, centrifuged, and the organic extract wastransferred to autosampler for LC-MS/MS analysis. Multiple reactionmonitoring (MRM) mode, scanning m/z 356→188 (compound 1h), m/z 371→203(compound 5Ha), m/z 389→221 (compound 5Hc), and m/z 309→171 (theinternal standard), was used to obtain the most sensitive signals. Thepharmacokinetic parameters were determined using non-compartmentalanalysis (WinNonlin, Pharsight Corporation, Mountain View, Calif.)

Results:

TABLE 4 Pharmacokinetic Parameters for Compounds Tested in vivo. 1h 2r5Ha 5Hc Route IV PO IV PO IV PO IV PO N^(a) 4    3 3   3 3  3 3  3 Dose(mg/kg) 2.5  10 2.5 4 5 10 5 10 CL^(b) (mL/min/kg) 7.7 ± 1.0 — 22 ± 13 —17 ± 3 — 13 ± 2 — Vss^(c) (L/kg) 4.9 ± 1.9 — 0.33 ± 0.25 —  1.4 ± 0.2 — 1.4 ± 0.2 — AUC^(d) (min * mg/mL) 279 ± 53  37 ± 20 139 ± 77    0.4 296± 46 65 ± 20 381 ± 65 160 ± 13 C_(max) ^(e) (ng/mL) 3816 ± 509  212 3.2± 1.6 3794 ± 1580 4198 ± 438 814 ± 255 3349 ± 686 1262 ± 362 F^(f) (%)3.3 0.2 11  21  ^(a)Numbers of rats. ^(b)Systemic clearance. ^(c)Volumeof distribution following intravenous dosing. ^(d)Area under the curvefollowing intravenous dosing, integrated drug concentration with respectto time and integrated drug concentration with respect to time followingoral dosing. ^(e)Maximum plasma concentration following intravenousdosing. ^(f)Percent oral bioavailability.

Modifying Substituted Methoxybenzoyl Aryl Thiazole (SMART) Molecules toImprove Oral Bioavailability. Many established tubulin targetinganticancer drugs like taxanes and vinblastine require intravenousadministration because of low oral bioavailability. Oral bioavailabilityis a complex parameter involving many chemical and physiologicalprocesses, such as solubility, permeability, and metabolic stability.The solubility of these tubulin inhibitors was improved by inserting anamino linker between the “A” and “B” rings as in 5a-c (FIG. 6), Table 3demonstrates that the NH bridged compounds (5a-c) had similar potency(35˜65 nM) as 1h with increased solubility (15 and 19 μg/mL for 5a and5c, respectively (FIG. 18), but they are over 20 fold more active thanABT-751 (Table 3 and FIG. 19 for the structure of ABT-751).

Rat pharmacokinetic studies were performed to study whether these newcompounds exhibited improved bioavailability compared to compound 1h(Table 4). The data clearly showed that 5Hc (HCl salt of 5c) exhibitedmore than 4.3-fold increased exposure (AUC) by the oral route ascompared to 1h, suggesting that improved aqueous solubility by the aminolinker successfully improved oral bioavailability. In addition, themaximal concentration (Cmax) of 5Ha and 5Hc by oral administration was814 and 1262 ng/mL, respectively. While Cmax of 1h was only 212 ng/mL.Overall, the bioavailability of 5Ha and 5Hc was increased from 3.3% of1h to 11% and 21%, respectively (Table 4). Compound 5Hc exhibitedmoderate clearance, moderate volume of distribution, and acceptable oralbioavailability. This data suggested that these new synthesized aminolinked compounds have the potency and PK profile to be developed as anew class of orally bioavailable antitubulin agents.

Example 11D In vitro Tubulin Polymerization Inhibition by Compounds ofthe Invention

In Vitro Tubulin Polymerization Assay. Bovine brain tubulin (0.4mg, >97% pure) (Cytoskeleton, Denver, Colo.) was mixed with 10 μM of thetest compounds and incubated in 100 μl of general tubulin buffer (80 mMPIPES, 2.0 mM MgCl₂, 0.5 mM EGTA, and 1 mM GTP) at pH 6.9. Theabsorbance of wavelength at 340 nm was monitored every 1 min for 20 minby the SYNERGY 4 Microplate Reader (Bio-Tek Instruments, Winooski, Vt.).The spectrophotometer was set at 37° C. for tubulin polymerization.

Results:

The inhibition of tubulin polymerization by selected potent compounds1c, 2j, 66a, and 5a was investigated by all three design strategies(alternative B-rings, novel linkers, and solubilizing moieties) andcompared with 1h. Bovine brain tubulin (>97% pure) was incubated withthe individual compounds (10 μM) to test their effect on tubulinpolymerization (FIG. 20). After 20 min incubation, tubulinpolymerization was inhibited 47% by 1h, as compared to vehicle. Both 1cand 2j inhibited 64% of polymerization at 20 min with differentinhibition patterns. Compounds 5a and 66a provided greater inhibitionsas 78% and 81%, respectively. These data suggest that these compoundsexhibit strong antitubulin polymerization activity that corresponds wellwith their cytotoxicity.

Example 11E Substituted Methoxy benzoyl Aryl Thiazole (SMART) CompoundsOvercome P-Glycoprotein Mediated Multidrug Resistance

The P-glycoprotein (P-gp) system appears to be a primary physiologicalmechanism of multidrug resistance (MDR) which acts as an ATP-dependentdrug efflux pump, actively removing a variety of structurally diversecytotoxic compounds. Enhanced efflux of these compounds reduces theirintracellular accumulation and so reduces their cytotoxicity. Therefore,novel compounds which are not susceptible to drug resistance could be ofhigh therapeutic and economic value. In addition to P-gp, clinicallyused antitubulin agents have other resistance mechanisms such as changesin microtubule dynamics and mutations in β-tubulin which are known tolimit sensitivity to the taxanes. The anti-tubulin compounds of theinvention were tested against an ovarian cancer cell line OVCAR-8(parent) and P-gp over-expressing NCI/ADR-RES cell line (Table 5).

Results:

TABLE 5 Antiproliferative Activity of Selected Compounds against P-gpover-expressed MDR cell lines. IC₅₀ (nM) Resistance Compound OVCAR-8NCI/ADR-RES factor  1c 33 ± 3   13 ± 0.8 0.4  2j 34 ± 2 14 ± 1 0.4 66a10 ± 3  4 ± 2 0.4  2r 26 ± 2 11 ± 2 0.4  5a 46 ± 6 27 0.6  5b 28 21 0.8 5c 44 ± 3 25 ± 6 0.6  1h 35 ± 2 13 ± 1 0.4 paclitaxel*  4.7 ± 0.1 6263± 634 1333 vinblastine  3.9 ± 0.1 582 ± 57 149 colchicine 17 ± 1 1113 ±79  65

Notably, the anti-tubulin compounds of the invention demonstratedequipotent anti-proliferative effects against OVCAR-8 and NCI/ADR-REScell lines, suggesting that they are not P-gp substrates and that theyfunction in a P-gp-independent manner. This feature is distinct fromthat of paclitaxel, vinblastine, and colchicine in NCI/ADR-RES cells.

A new series of tubulin polymerization inhibitors with acceptable oralbioavailability and equi-potent activity in multidrug resistant tumorcell lines has been discovered. Medicinal chemistry efforts startingfrom optimizing SMART compound 1h. Chemical modifications of differentsubstituted aryl in “B” ring and linkages between “B” and “C” rings wereinvestigated based on biological evaluation against cancer cells invitro. SAR studies revealed that optimal “B” rings include pyridine(1c), thiophene (1f), and furan (1d) which maintain excellent in vitropotency. Replacing carbonyl linker with cyanoimine (2j) between “B” and“C” ring will increase the activity. Structure modifications to increaseaqueous solubility and bioavailability were performed. Introducing anamino between “A” and “B” rings gave us compounds 5a-c, which showedsimilar in vitro antiproliferative potency against tested cancer cellsas well as MDR(+) and MDR(−) cell lines, furthermore, the solubility andin vivo bioavailability were improved greatly over those of the 1h.Therefore, these new anti-tubulin compounds represent a new family ofcompounds that may be very useful in the treatment of cancer.

Example 12 Antiproliferative Activity of Compounds of this Invention

The antiproliferative activity of analogs prepared by the methods of theinvention are shown in Tables 6 and 6A.

TABLE 6 IC₅₀ ± SEM (nM) MES- MES- OVCAR- NCI/ADR- ID LNCaP PC-3 DU 145PPC-1 A375 B16-F1 WM164 SA SA/Dx5 8 RES Paclitaxel 1.7 4.8 5.1 2.3 12 172.7 6.6 4.7 6263 Vinblastine 1.1 2.1 1.8 1.1 1 4.7 1.4 16 3.9 582Colchicine 16 11 10 20 20 29 8.4 22 17 1113 1k 101 101 140 84 100 245220 2k 6 13 12 8 33 43 11 19 34 12 2m 19 8.7 6.9 6.2 11 21 2n 101 131143 99 210 290 2o 65 73 121 73 38 42 2p >10000 2385 1899 1079 2200 165602q >10000 >10000 >10000 >10000 >20000 >20000 5c-HCl 53 53 70 43 6d 703908 1637 929 *ND: not determined

TABLE 6A IC₅₀ (nM) Structure ID LNCaP PC-3 DU 145 PPC-1 A375

8 346 704 580 230 318

9 ~10000 ~10000 ~10000 ~10000

10 658 786 839 701 1111

11 >10000 >10000 ~10000 ~10000 3470

12 >10000 >10000 >10000 >10000 >10000

13 >10000 >10000 >10000 >10000 >10000

14 >10000 >10000 >10000 >10000 >10000

16 >10000 >10000 >10000 >10000 15200

17 2100 1900 2600 1300 4300

18 ~10000 ~10000 ~10000 ~10000

19 >20000 >20000 >20000 >20000 >20000

20 1452 >10000 642 633 2300

21 314 403 435 216 383

22 >20000 >20000 >20000 >20000 >20000

23 ~10000 ~10000 ~10000 ~10000

24 >10000 >10000 >10000 >10000 >10000

25 48 44 24 13 20

26 23 16 16 15 11

29 1788 >10000 >10000 >10000 >10000

30 >10000 >10000 >10000 >10000 >10000

32 1664 229 4601 1170 2700

33 >2000 >2000 >2000 >2000 9800

34 >10000 >10000 >10000 >10000 >10000

35 1500 40100 21900 15000

39 4300 32500 16800 21400

40 13400 19600 18400 6200

41 15750 18170 17040 >20000

42 43590 23790 24880 >20000 43 12690 14720 17210 >20000

17ya 12 10 17 21 17.35

17yaa 233.7 148.3 592.1 208.9 481.2

15xaa 1068 2628 5917 4575 1800

16xaa >10000 >10000 >10000 >10000 >10000 IC50 (nM) MES- MES- OVCAR-NCl/AD Structure ID B16-F1 WM164 SA SA/Dx5 8 R-RES

8 570 404

9

10 2127 661

11 4900 4700

12 >10000 >10000

13 >10000

14 >10000

16 6900

17 9800

18

19 >20000

20 3100 1300

21 924 408

22 >20000

23

24 >10000 >10000

25 38

26 14

29 >10000

30 >10000

32 >10000 2600

33 >20000

34 >10000 >10000

35

39

40

41

42 43

17ya 32.94 12.08

17yaa 538.7 467.6

15xaa 1390 1700

16xaa >10000 >10000

Example 13 Biological Evaluation of Isoquinoline Derivatives of thisInvention Cell Culture.

LNCaP, PC-3, DU-145, PPC-1, MES-SA, and MES-SA/DX5 were originallyobtained from ATCC (Rockville, Md.). All cells obtained from ATCC wereimmediately expanded and frozen down such that all cell lines could berestarted every 2-3 months from a frozen vial of the same batch ofcells. For the in vivo xenograft studies, PC-3 was authenticated atResearch Animal Diagnostic Laboratory (Columbia, Mo.) within four monthsbefore studies. Inter-species contamination was tested by PCR and theidentity of the cell lines was verified by generating a genetic profile.MES-SA and MES-SA/DX5 were maintained in McCoy's 5A Medium containing 2mM L-glutamine supplemented with 10% fetal bovine serum (FBS). All othercells were maintained in RPMI-1640 medium with 2 mM L-glutamine and 10%FBS.

Growth Inhibition Assay.

The cytotoxic or anti-proliferative activity of test compounds wasinvestigated in several cell lines using the sulforhodamine B (SRB)assay. Cultured cells were plated into 96-well plates and incubated withmedium containing different concentrations of the test compounds for 96h. Cells were stained with SRB solution. The optical density wasdetermined at 540 nm on a microplate reader (Dynex Technologies,Chantilly, Va.). Plots of percent inhibition of cell growth versus drugconcentration were constructed, and the concentration that inhibitedcell growth by 50% relative to the untreated control (IC₅₀) wasdetermined by nonlinear least squares regression using WinNonlinsoftware (Pharsight Corporation, Cary, N.C.).

Cell Cycle Analysis.

Cell cycle distribution was determined by propidium iodide (PI)staining. Treated cells were washed with PBS and fixed with 70% ice-coldethanol overnight. Fixed cells were then stained with 20 μg/mL of PI inthe presence of RNase A (300 μg/mL) at 37° C. for 30 min. Cell cycledistribution was analyzed by fluorescence-activated cell sorting (FACS)analysis core services at the University of Tennessee Health ScienceCenter, Tenn.

In Vitro Metabolism Studies.

For both phase I, the incubation mixture, in 65 mM potassium phosphatebuffer (pH 7.4), consisted of 1 mg/mL liver microsomal proteins, 3 mMNADPH, and 0.5 μM test compound. The concentration of methanol (used fordissolving the substrate) was 1% (v/v). Total volume of the incubationwas 200 μL and the reaction mixtures were incubated at 37° C. Togenerate the stability curves for test compounds different incubationswere stopped at 10, 20, 30, 60, and 90 minutes for analysis of compoundsremaining. All reactions were stopped by the addition of 200 μL ice-coldacetonitrile. Subsequently, the samples were then centrifuged at 3000 gfor 5 min and supernatant was analyzed by LC-MS/MS.

Pharmacokinetic Studies in Mice.

Male ICR mice (5-6 weeks, 20-25 g) were used. For 6a, 6b, and 6c, adose, 5 mg/kg, was administered via the i.v., i.p., and p.o. route. I.v.doses were administered via the tail vein. Oral doses were administeredby gavage. At each time point, three to four mice were euthanized byisoflurane (Baxter Healthcare, Deerfield, Ill.) and blood samples (up to600 μL each) were taken from the posterior vena cava. Plasma sampleswere stored at −20° C. prior to analysis. Plasma proteins wereprecipitated by the addition of acetonitrile (150 μL, containing theinternal standard) to 100 μL of mouse plasma. Samples were vortexed andthen centrifuged at 8000 g for 10 min. The supernatant was transferredto a clean vial for injection into the mass spectrometer for analysis.

In Vivo Antitumor Efficacy Study.

PC-3 cells (2.5×10⁶ cells/site) plus Matrigel (BD biosciences, San Jose,Calif.) were injected subcutaneously into flanks of male nu/nu mice.Tumor size was measured using calipers every 2-4 days and calculated asV=π/6×(length)×(width)^(2 [)13]. When tumors reached a volume ofapproximately 100˜150 mm³, drug treatment was initiated. The controlgroup was treated with vehicle (20% Captex200 in Tween80). During thetreatment, tumor size and body weights were measured every 2-4 days.

White Blood Cell Counting.

Whole blood was obtained from nude mice at the end of efficacy study. Tocount white blood cells (WBC) using a hemacytometer, 10 μL of wholeblood sample was diluted with the 190 μL of 2% acetic acid. With properlight adjustment, the leukocytes appeared as dark dots on thehemacytometer. WBC in each sample was counted twice within one hoursfollowing dilution and average was calculated.

Results

7. Anticancer efficacy of isoquinoline compounds in different cancercell lines and MDR cell lines mediated by P-glycoprotein

IC₅₀ (nM) 6a 6b 6c Vinblastine Docetaxel LNCaP 80.6 ± 17.1  98.1 ± 17.938.3 ± 9.7 3.4 ± 0.9 4.7 ± 1.3 PC-3 64.4 ± 12.2 71.8 ± 9.1 25.6 ± 8.31.4 ± 0.3 6.3 ± 0.4 DU-145 91.7 ± 10.2 113.4 ± 21.4  46.6 ± 13.8 2.6 ±1.0 5.2 ± 1.0 PPC-1 60.6 ± 3.4   47.9 ± 10.0 27.7 ± 4.5 1.1 ± 0.4 2.7 ±1.0 P-gp MES-SA 78.2 ± 1.8  129.8 ± 38.0 35.6 ± 2.8 2.3 ± 0.8 5.9 ± 1.1MES-SA/DX5 119.4 ± 0.4  177.8 ± 32.8 59.2 ± 0.1 45.7 ± 5.3  76.4 ± 8.7 Resistance factor 1.5 1.4 1.7 20 13 NOTE: P-gp is over-expressed inMES-SA/DX5. The resistance factor (RF) was calculated as the ratio ofIC₅₀ values for the resistant cell subline to that of the parental cellline. All experiments were performed at least in three replicates. NDnot determined.

TABLE 8 Compound 6a, 6b, and 6c arrested PC-3 cells in G₂M phase. G₂Mphase arrest EC₅₀ (nM) 6a 53.4 6b 91.9 6c 23.3

TABLE 9 Summary Half life (Phase I pathway) of 6a, 6b, and 6c in mouse,rat, hamster, rabbit, guinea pig, dog, monkey, and human livermicrosomes. T ½ (min) 6a 6b 6c Mouse 3.4 10 13 Rat 12 9 14 Hamster 6 1120 Rabbit 17 16 16 Guinea pig 15 15 8 Dog 13 30 29 Monkey 16 13 9 Human32 40 47

TABLE 10 Summary of pharmacokinetic properties of Compound 6a, 6b, and6c in mice.

MW 410.5 359.4 338.4 IV CL (mL*min⁻¹kg⁻¹) 5mg/kg 51 14 30 IV V_(d)(L*kg⁻¹) 5mg/kg 2.3 1.1 1.8 IP C_(max) (ng/mL) 5mg/kg 678.4 1500 1100 IPAUC (min*μg/mL) 5mg/kg 59 218 55 IP Bioavailability F_(ip)% 60 60 33 POC_(max) (ng/mL) 5mg/kg 6.7 50 50 AUC (min*μg/mL) 5mg/kg 5 7 4 POBioavailability F_(po)% 5 2.1 2.7

Efficacy and tolerability of 6b and 6c was measured in xenograft modelsafter i.p. injection (FIG. 34). PC-3 xenografts were treated withvehicle (qd), 6b (40 mg/kg, qd), or 6c (40 mg/kg, qd) for 3 weeks.Dosing vehicles were composed of 20% Captex200 in Tween80. The tumorvolumes (mm³) were plotted against time and are the means±SD from eightanimals. The tumor volumes and survival rates or body weights are shownin FIG. 34A. The liver size (g) of each nude mouse was measured after 3weeks treatment and is shown in FIG. 34B. The number of white bloodcells was counted in whole blood collected from animal after 3 weekstreatment and is shown in FIG. 34C.

Example 14 Antiproliferative Activity of Selected ABI Compounds of thisInvention Cell Culture Cytotoxicity Assay Materials and Methods

The antiproliferative activity of the ABI compounds in three melanomacell lines (A375 and WM-164, human melanoma cell line; B16-F1, mousemelanoma cell line) and four human prostate cancer cell lines (LNCaP, DU145, PC-3, and PPC-1) were studied. All these cell lines were purchasedfrom ATCC (American Type Culture Collection, Manassas, Va.) except thePPC-1 cell line. MDA-MB-435 and MDA-MB-435/LCCMDR1 cells were kindlyprovided by Dr. Robert Clarke at Georgetown University School ofMedicine, Washington, D.C. Melanoma cells were cultured in DMEM (CellgroMediatech, Inc., Herndon, Va.) and prostate cancer cells were culturedin RPMI 1640 (Cellgro Mediatech, Inc., Herndon, Va.) supplemented with10% FBS (Cellgro Mediatech). Cultures were maintained at 37° C. in ahumidified atmosphere containing 5% CO₂. 1000 to 5000 cells were platedinto each well of 96-well plates depending on growth rate and exposed todifferent concentrations of a test compound for 48 h (fast growingmelanoma cells) or 96 h (slow growing prostate cancer cells) in three tofive replicates. Cell numbers at the end of the drug treatment weremeasured by the sulforhodamine B (SRB) assay. Briefly, the cells werefixed with 10% trichloroacetic acid and stained with 0.4% SRB, and theabsorbances at 540 nm were measured using a plate reader (DYNEXTechnologies, Chantilly, Va.). Percentages of cell survival versus drugconcentrations were plotted, and the IC₅₀ (concentration that inhibitedcell growth by 50% of untreated control) values were obtained bynonlinear regression analysis using GraphPad Prism (GraphPad Software,San Diego, Calif.).

Results

The results of the in vitro antiproliferative activities of thecompounds of this invention using three melanoma cell lines (one murinemelanoma cell line, B 16-F1, and two human metastatic melanoma celllines, A375 and WM-164) and four human prostate cancer cell lines(LNCaP, PC-3, Du 145, and PPC-1) are summarized in Tables 11-13.

TABLE 11 In vitro growth inhibitory effects of compounds without A ringsubstitutions. IC₅₀(nM) Structure ID R A375 B16-F1 WM164 LNCaP PC-3 Du145 PPC-1

12aa 12ab 12ac 12ad 12ae 12af 12ag 12ah 12ai 3,4,5-(OME)₃ 4-OMe 3-OMe3,5-(OMe)₂ 3,4-(OMe)₂ 4-F 3-F 4-Me 3-Me 160 >10000 >10000 2800 >10000580 >10000 >10000 >10000 120 >10000 >10000 5400 >10000930 >10000 >10000 >10000 10 >10000 >10000 2100 >10000630 >10000 >10000 >10000 152 >10000 >10000 3611 >10000613 >10000 >10000 >10000 288 >10000 >10000 3274 >100002197 >10000 >10000 >10000 196 >10000 >10000 2590 >10000846 >10000 >10000 >10000 133 >10000 >10000 2129 >10000 575 >10000 >10000>10000

12aba 12aaa 4-OMe3,4,5-(OMe)₃ >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000>10000

10a 10x 10j H 4-NO₂4-OBn >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000>10000

From Table 11, compounds 12aa-12ai showed moderate activity with IC₅₀values in the μM range (average of all seven cell lines). The mostpotent compound of this series was 12aa with an average IC₅₀ value of160 nM. The removal of one of the methoxy groups from the3,4,5-trimethoxy on the C ring (12ad, 12ae) led to a significant loss ofactivity (IC₅₀>10 μM for 12ae and an average IC₅₀ of 3.1 μM for 12ad).Compound with 4-fluoro on the C ring (12af) also showed relatively goodactivity (IC₅₀=0.91 μM), a finding that has an important implication,because replacing the trimethoxy moiety with a 4-fluoro group mayprovide good activity and improved metabolic stability. The position ofthe fluorine on the C ring was critical for activity because a shiftfrom 4-fluoro to 3-fluoro resulted in a total loss of activity (IC₅₀>10μM for 12ag compared with 0.91 μM for 12af). This result suggested thata potential hydrogen bond donor is present close to the 4-position ofthis ring.

As clearly indicated in Table 11, the positions of the A and C ringswere critical. A simple shift of the C-ring moiety from position 4 toposition 1 in the imidazole ring (B ring) resulted in total loss ofactivity (IC₅₀>10 μM for 12aba, 12aaa, 10a, 10x, 10j).

TABLE 12 In vitro growth inhibitory effects of compounds withsubstitutions on A ring. IC₅₀ ± SEM (nM) ID R¹ R² A375 B16-F1 WM164LNCaP

12ba 12ca 12cb 12da 12db 12db-HCl 12dc 12ea 12eb 12fa 12fb 13fa 12ga12gb 12ha 12hb 12ia 12ib 13ea 12ja 12jb 12ka 12kb 12kc 12la 12pa 13haColchicine 4-F 4-OMe 4-OMe 4-Me 4-Me   4-Me 3,4,5-(OMe)₃ 3,4,5-(OMe)₃4-Cl 4-Cl 4-Cl 4-N(Me)₂ 4-N(Me)₂ 3,4-(OMe)₂ 3,4-(OMe) 2-CF₃ 2-CF₃3,4,5-(OH)₃ 4-OBn 4-OBn 4-OH 4-OH 4-OH 4-Br 4-CF3 3,4-(OH)₂  3,4,5-(OMe)₃ 3,4,5-(OMe)₃ 4-F 3,4,5-(OMe)₃ 4-F   3,5-(OMe)₂-4-OH3,4,5-(OMe)₃ 4-F 3,4,5-(OMe)₃ 4-F 3,4,5-(OH)₃ 3,4,5-(OMe)₃ 4-F3,4,5-(OMe)₃ 4-F 3,4,5-(OMe)₃ 4-F 3,4,5-(OH)₃ 3,4,5-(OMe)₃ 4-F3,4,5-(OMe)₃ 4-F 3-OH,4,5-(OMe)₂ 3,4,5-(OMe)₃ 3,4,5-(OMe)₃ 3,4,5-(OH)₃  205 ± 119 30 ± 5  31 ± 5  9 ± 2 143 ± 13  108 ± 11   105  4800 >10000 43± 5  52 ± 4   3900 82 ± 9  56 ± 7  113 ± 14  10000 >10000 >10000 >10000 5200 93 ± 8  1600 10000 10000   32   163.1 >10000 20 ± 3  320 ± 41  108± 12  63 ± 7  46 ± 5  222 ± 10  297 ± 23   387 >10000 >10000 168 ± 14 73 ± 6   1810 361 ± 29  129 ± 11  1400 ± 200   4210 >10000 >10000 >1000010000 117 ± 16   2400 >10000  5600   74   468.7 >10000 29 ± 5  73 ± 1831 ± 4  28 ± 3  8 ± 2 156 ± 9  112 ± 9   123 >10000 >10000 26 ± 3  74 ±9  2100 80 ± 11 62 ± 8  191 ± 18  1400 >10000 >10000 >10000 5500 90 ± 121800 >10000 6400  36  175 >10000 ND 98 ± 2  31 ± 1  28 ± 2  12 ± 1  45 ±2  ND  134 >10000 >10000 24 ± 1  19 ± 2  10000 58 ± 2  57 ± 6  121 ± 10  2533 >10000 >10000 >10000  2786 44 ± 7  ND 10000     34  134 ND 16 ± 4IC₅₀ ± SEM (nM) NCl/ADR- ID PC-3 DU 145 PPC-1 OVCAR-8 RES

12ba 12ca 12cb 12da 12db 12db-HCl 12dc 12ea 12eb 12fa 12fb 13fa 12ga12gb 12ha 12hb 12ia 12ib 13ea 12ja 12jb 12ka 12kb 12kc 12la 12pa 13haColchicine 169 ± 12  45 ± 1  31 ± 2    9 ± 0.4 56 ± 3  ND 127 >10000 >10000 35 ± 1  31 ± 2  10000 92 ± 4  81 ± 3 203 ± 710000 >10000 >10000 >10000 10000  79 ± 0.4 ND >10000     36  127 ND 11 ±1  132 ± 24   48 ± 0.5 41 ± 38  15 ± 0.5 78 ± 5  ND  174 >10000 >10000 36 ± 0.4 65 ± 1  10000 95 ± 1   72 ± 0.4 168 ± 15  10000 >10000 >10000 >10000 10000 60 ± 3  ND >10000     49  174 ND 10 ±2  81 ± 1   34 ± 0.3 29 ± 1   11 ± 0.1 54 ± 1  ND  110 >10000 >10000  26± 0.2 52 ± 1  >10000  67 ± 0.7  4± 0.3 117 ± 1  2172 ±48  >10000 >10000 >10000 2844  43 ± 0.2 ND >10000    33  110 ND 20 ± 1                  47                   19 ND—not determined

From Table 12 compounds with 3,4,5-trimethoxy and 4-fluoro substitutionson the C ring showed good activity with different substitutions on the Aring. These compounds demonstrated excellent antiproliferative activitywith IC₅₀ values as low as 8.0 nM on WM164 cell line (12da). In general,compounds incorporating a single substituent on the para-position of theA ring were more potent as can be seen from the activities of 12ca,12cb, 12da, 12 db, 12fa, 12fb, 12ga, and 12gb (IC₅₀=7.9-110 nM). 12db-HCl salt (IC₅₀=172 nM) showed slightly diminished activity comparedwith the corresponding free base 12 db (IC₅₀=109 nM). Compound 12fb(IC₅₀=63.7 nM), with a single halogen substituent in the para-positionof the A and C rings, demonstrated potent and was devoid of a methoxymoiety. Compounds with 3,4,5-trimethoxy substituents on the A ring lostactivity completely (IC₅₀>10 μM for 12ea, 12eb), suggesting verydifferent binding environments near the A ring and C ring. Removal ofthe 5-methoxy substituent from the A-ring improved activitysignificantly (IC₅₀=330 nM and >10 μM for 12ha, 12ea respectively).Demethylation of the 3,4,5-trimethoxy decreased activity sharply from 43nM (12fa) to 3.89 μM (13fa). Similar results were observed for 13ea,12ka, 12 kb, and 13ha due to the demethylation of substituents on eitherthe A or C ring. Electron-donating groups (4-methoxy, 4-dimethylamino,4-methyl) and electron-withdrawing groups (4-chloro, 2-trifluoromethyl)on the A ring did not show substantial differences in activity. Theintroduction of a trifluoromethyl group at the ortho position of the Aring caused complete loss of activity (IC₅₀>10 μM for 12ia, 12ib). Thepresence of a benzoyloxy group at the para position of A ring (IC₅₀=75nM for 12jb) resulted in a 440-fold increase in activity when comparedwith the para-hydroxy compound 12 kb (IC₅₀=33 μM). It is worthwhile tonote that compound 12jb, with the 4-fluoro in the C ring, has betteractivity than does its counterpart 12ja, which has a 3,4,5-trimethoxygroup in the C ring (IC₅₀ is 75 nM for 12jb, and 7.3 μM for 12ja).

TABLE 13 In vitro growth inhibitory effects of compounds with protectionon B ring. IC₅₀± SEM (nM) Structure ID R¹ R² R³ A375 B16-F1 WM164 LNCaPPC-3 Du 145 PPC-1

11ab 11ac 11ah 11af 11ag 11cb 11db 11ea   11eb   11fb 11ga   11gb 11ha  11hb   11ia   11ib 11jb 12dab   12cba 12daa   12gba H H H H H 4-OMe 4-Me3,4,5- (OMe)₃ 3,4,5- (OMe)₃ 4-Cl 4-N(Me)₂   4-N(Me)₂ 3,4- (OMe)₂ 3,4-(OMe)₂ 2-CF₃   2-CF₃ 4-OBn 4-Me   4-OMe 4-Me   4-N(Me)₂ 4-OMe 3-OMe 4-Me4-F 3-F 4-F 4-F 3,4,5- (OMe)₃ 4-F   4-F 3,4,5- (OMe)₃ 4-F 3,4,5- (OMe)₃4-F   3,4,5- (OMe)₃ 4-F 4-F 3,4,5- (OMe)₃ 4-F 3,4,5- (OMe)₃ 4-F SO₂PhSO₂Ph SO₂Ph SO₂Ph SO₂Ph SO₂Ph SO₂Ph SO₂Ph   SO₂Ph   SO₂Ph SO₂Ph   SO₂PhSO₂Ph   SO₂Ph   SO₂Ph   SO₂Ph SO₂Ph Me   Me CH₂Ph  SO₂PhOMe >10000 >10000 >10000 630 ± 72  >10000 36 ± 5  113 ± 14  >10000  3840   88 ± 9  162 ± 13    55 ± 7  192 ± 15    960 ± 59    >10000  >10000 64 ± 7   32   >10000     ~100 >10000 >10000 >10000 946 ±86  >10000 71 ± 8  287 ± 31  >10000   >10000   107 ± 12  1200 ± 90   242 ± 26  970 ± 68    2000 ± 400    >10000   >10000 110 ± 15  134  >10000     ~100 >10000 >10000 >10000 596 ± 61  >10000 43 ± 6  107 ±14  >10000   >10000   70 ± 6  308 ± 32    56 ± 4  139 ± 15    1400 ± 30   >10000   >10000 48 ± 5  40   >10000     ~100 >10000 >10000 >10000  573 >10000 31 ± 2  55 ± 3  >10000   >10000   48 ± 1  62 ± 2    56 ± 6 114 ± 6    1915 ± 77    >10000   >10000 35 ± 1   32   >10000 683.2   73.2 >10000 >10000 >10000  2233 >10000 33 ± 2  80 ± 1  >10000   >10000  76 ± 2  93 ± 6    83 ± 3  197 ± 9    10000   >10000   >10000  75 ± 0.5  46   >10000 465.8   44.14 >10000 >10000 >10000   846 >10000 52 ± 3  80± 1  >10000   >10000   64 ± 1  99 ± 2     74 ± 0.5 144 ± 29     3312  >10000   >10000 58 ± 1    36   >10000  1501  129.4 >10000 >10000 >10000   575 >10000  32 ± 0.7 57 ± 1  >10000  >10000   54 ± 1   72 ± 0.4    48 ± 0.3 117 ± 2    1441 ± 49    >10000  >10000  38 ± 0.2   28   >10000 777.9    63.4

From Table 13, compounds with a phenylsulfonyl protection group attachedto the nitrogen of the imidazole ring (11cb, 11 db, 11fb, 11ga, 11gb,11ha, 11jb) were also very active with IC₅₀ in the nM range (Table 13).Generally the activities of these compounds are comparable to theircorresponding unprotected counterparts as exemplified by comparing theactivities of 11cb (43 nM), 11 db (111 nM), 11fb (72 nM), 11ga (285 nM),11gb (87 nM), 11ha (268 nM), and 11jb (61 nM) with their correspondingunprotected counterparts 12cb (36 nM), 12 db (109 nM), 12fb (64 nM),12ga (131 nM), 12gb (72 nM), 12ha (330 nM), and 12jb (75 nM). Othercompounds (11ab-11ag, 11ea, 11eb, 11hb, 11ia, and 111b, 1-50 μM) weregenerally much less active, also in line with their counterparts(12ab-12ag, 12ea, 12eb, 12hb, 12ia, and 12ib, 1-50 μM).

Example 15 Activity of Aryl-Benzoyl-Imidazole (ABI) Compounds inDrug-Resistant Melanoma Cells

P-glycoprotein (Pgp)-mediated drug efflux represents a major mechanismfor cancer cells to prevent the build up of effective anticancerintracellular drug concentrations. The activity of the ABI compoundswere compared against multidrug-resistant (MDR) melanoma cells(MDA-MB-435/LCCMDR1) and their parental nonresistant cancer cells(MDA-MB-435). Although MDA-MB-435 was originally designated as a breastcancer cell line, it has been shown definitively to originate from theM14 melanoma cell line. Compounds 12da, 12fb, 12cb, 11cb, and 11fbtogether with other tubulin-targeting agents including colchicine,paclitaxel, and vinblastine were tested on both the MDR melanoma cellline and its parental melanoma cell line (Table 14). Paclitaxel andvinblastine are clinically used anticancer drugs known to target celltubulin. Although colchicine is not an FDA-approved drug for cancertreatment, its prodrug, ZD6126, is in clinical trial for solid tumors.Bortezomib is the first therapeutic proteasome inhibitor and wasapproved in 2003 by the FDA for use in multiple myeloma. ABT-751 isknown to target the tubulin colchicine binding site. It is a promisingdrug candidate in clinical trial for children with relapsed orrefractory neuroblastoma. Compounds 12da, 12fb, 12cb, 11cb, 11fb hadmuch better resistance indices (3.0 for 12da, 0.9 for 12fb, 1.3 for12cb, 0.8 for 11cb, 0.7 for 11fb) than colchicine (65.8), paclitaxel(69.3), and vinblastine (27.5). Although colchicine, paclitaxel, andvinblastine showed excellent activity in nonresistant melanoma celllines (0.5-10 nM), these compounds were significantly less potent in theMDR melanoma cell line (277-658 nM). In contrast, 12cb, 11cb, 11M hadessentially equivalent potency on both MDR (15 nM, 38 nM, 30 nM, 30 nM,35 nM for 12da, 12fb, 12cb, 11cb and 11M respectively) and nonresistantmelanoma cell lines (5 nM, 41 nM, 24 nM, 38 nM, 50 nM for 12da, 12M,12cb, 11cb and 11M respectively). Compound 12da was more active thanpaclitaxel and colchicine on A375 and WM-164 cells.

TABLE 14 In vitro growth inhibitory effects of the ABI compounds incomparison to other anticancer drugs on multidrug-resistant melanomacell line (MDR cell) and the matching sensitive parent cell line (NormalMelanoma cell). IC₅₀ ± SEM (nM) (n = 3) Tubulin MDA- MDA-MB- CompoundWM- binding MB- 435/ Resistance ID A375 B16-F1 164 (μm) 435 LCC6MDR1index* 12da  9 ± 2 46 ± 5  8 ± 2 0.2 ± 0.1  5 ± 1 15 ± 2 3.0 12fb 52 ± 473 ± 6 74 ± 9 3.9 ± 2.1 41 ± 2 38 ± 2 0.9 12cb 31 ± 5 63 ± 7 28 ± 3 3.4± 1.5 24 ± 2 30 ± 4 1.3 11cb 36 ± 5 71 ± 8 43 ± 6 ND 38 ± 3 30 ± 2 0.811fb 88 ± 9 107 ± 12 74 ± 8 ND 50 ± 6 35 ± 3 0.7 Paclitaxel 12 ± 3 17 ±2 18 ± 3 N/A  4 ± 1 277 ± 41 69.3 Vinblastine  1.1 ± 0.2  4.7 ± 0.7  0.6± 0.1 ND  0.4 ± 0.1 11 ± 1 27.5 Colchicine 20 ± 3 29 ± 5 10 ± 2 1.8 ±0.5 10 ± 1 658 ± 50 65.8 Bortezomib  8 ± 1 24 ± 2  8 ± 1 ND ND ND NDABT-751 1111 ± 108 2127 ± 351 661 ± 56 ND ND ND ND *Resistance indexeswere calculated by dividing IC₅₀ values on multidrug-resistant cell lineMDA-MB-435/LCC6MDR1 by IC₅₀ values on the matching sensitive parentalcell line MDA-MB-435. Abbreviations: N/A, value not available; ND, notdetermined.

The results of Table 14 showed that cell line MDA-MB-435/LCCMDR1 wasvery resistant to colchicine, paclitaxel, and vinblastine. But the ABIsof this invention showed equal potency to the drug-resistant cell lineand the sensitive parent cell line. This result strongly suggests thatABIs are not substrates for P-gp. Thus, they overcame the multidrugresistance found in MDA-MB-435/LCCMDR1 cells. The dose response curvesare shown in FIG. 21 for 12M, 12da, and 12cb.

Example 16 In Vitro Microtubule Polymerization Assay Materials andMethods

Bovine brain tubulin (0.4 mg) (Cytoskeleton, Denver, Colo.) was mixedwith 10 μM of the test compound and incubated in 110 μl of generaltubulin buffer (80 mM PIPES, 2.0 mM MgCl₂, 0.5 mM EGTA, and 1 mM GTP) atpH 6.9. The absorbance at 340 nm was monitored every 1 min for 15 min bythe SYNERGY 4 Microplate Reader (Bio-Tek Instruments, Winooski, Vt.).The spectrophotometer was set at 37° C. for tubulin polymerization.

Results

The inhibition of tublin polymerization by Aryl-Benzoyl-Imidazole (ABI)compounds was examined. Bovine brain tubulin (>97% pure) was incubatedwith three potent ABI compounds, 12cb, 12da, and 12 db at aconcentration of 10 μM, to determine the effect of these ABI compoundson tubulin polymerization (FIG. 22). Tubulin polymerization wascompletely inhibited by compound 12da, while ˜80% inhibition wasobserved during incubation with compounds 12cb and 12 db.

This microtubule destabilization effect was similar to that ofcolchicine and vinblastine but was opposite to that of paclitaxel. Theresults not only confirmed that ABIs can directly interact with tubulinbut also suggested that they may share the same binding site withcolchicine (or vinblastine).

Example 17 Melanoma Inhibition In Vitro Materials and Methods

B16-F1 melanoma cells were plated at a colony-forming density (2000cells per well on six-well plates) on top of 0.8% base agar. Cells weregrown in 0.4% agar together with DMEM medium supplemented with fetalbovine serum and an antibiotic-antimycotic solution at 37° C. in anatmosphere of 95% air and 5% CO₂. Cells were treated with compounds12da, 12cb and 12fb at different concentrations (20, 100, and 500 nM).Compounds were added to the media from 1-mM DMSO stock solutions, and acorresponding dilution of DMSO was used as control. Cells were grown for14 days. Plates were photographed, and the number of colonies wasmeasured by Artek 880 Automated Colony Counter (Artek SystemsCorporation, Farmingdale, N.Y.).

Results

Four representative photos are shown in FIG. 23. After 14 days ofincubation, about 130 detectable colonies (diameter larger than 100 μm)were formed in controls (no treatment).

Compounds 12cb and 12da effectively inhibited B16-F1 melanoma colonyformation even at the lowest tested concentration, 20 nM (p<0.05compared with control). 12fb showed effective inhibition at 100 nM. Allthree tested compounds showed complete inhibition of colony formation at0.5 μM, further proving ABIs' antimelanoma efficacy.

Example 18 In Vivo Anti-Tumor Activity Materials and Methods

Animals: Female C57/BL mice, age 4-6 weeks, were purchased from HarlanLaboratories (Harlan Laboratories Inc., Indianapolis, Ind.). The animalhousing met the Association for Assessment and Accreditation andLaboratory Animal Care specifications. All of the procedures wereconducted in accordance with guidelines of our Institutional Animal Careand Use Committee.

In vivo evaluation of efficacy. Mouse melanoma B16-F1 cells wereprepared in FBS-free DMEM medium (Cellgro Mediatech) at a concentrationof 5×10⁶ viable cells/mL. The cell suspension (100 μL) was injectedsubcutaneously in the right dorsal flank of each mouse. When tumor sizereached about 100-150 mm³, about 7 days after cell inoculation, all micebearing tumors were divided into control and treatment groups based ontumor size (n=5 per group). Each group had similar average tumor size.Mice in control groups (negative control) were injectedintraperitoneally with 50 μL vehicle solution only or DTIC at 60 mg/kg(positive control) once daily. Tumor volume was measured every 2 dayswith a traceable electronic digital caliper (Fisher Scientific, Inc.,Pittsburgh, Pa.) and calculated using the formula a×b²×0.5, where a andb represented the larger and smaller diameters, respectively. Tumorvolume was expressed in cubic millimeters. Data were expressed asmean±SE for each group and plotted as a function of time. Percentagetumor reduction at the conclusion of the experiment (14 days afterstarting treatment) was calculated with the formula100−100×[(T−T₀)/(C−C₀)], where T represents mean tumor volume of atreated group on a specific day, T₀ represents mean tumor volume of thesame group on the first day of treatment, C represents mean tumor volumeof a control on a specific day, and C₀ represents mean tumor volume ofthe same group on the first day of treatment. Animal activity andaverage body weight of each group were monitored during the entireexperiment period to assess compound toxicity. At the end of treatment,all mice were euthanized by CO₂ followed by cervical dislocation, andtumors were harvested for further studies.

Results

To evaluate efficacy of ABI analogs in vivo, we tested the antitumoractivity of compound 12cb on mice melanoma B16-F1 xenograph. againstDTIC, the gold standard in malignant melanoma treatment, was used as apositive control (FIG. 24A). Twenty female C57/BL mice were divided intofour groups: a vehicle control group, a DTIC (60 mg/kg) treatment group,a 12cb (10 mg/kg) treatment group, and a 12cb (30 mg/kg) treatmentgroup. Each mouse was injected with 0.5 million B16-F1 melanoma cellssubcutaneously. Seven days after tumor inoculation, treatment startedwith each compound injected intraperitoneally daily (FIG. 24). Tumorvolume was significantly (p<0.05) reduced 47%, 51%, and 73% for 12cb (10mg/kg), DTIC (60 mg/kg), and 12cb (30 mg/kg), respectively, after 14days of treatment. No significant weight loss was observed in any of thetreatment groups during the experiment.

Two dose levels, 15 and 45 mg/kg, were chosen. DTIC at 60 mg/kg was usedas a positive control. B16-F1 melanoma allograft model on C57BL/6 micewas first chosen for study. After 13 days of treatment. (FIG. 24B),compound 12fb inhibited melanoma tumor growth (TGI value) by 32% at 15mg/kg and 82% at 45 mg/kg. Student's t test p value of 12fb at 45 mg/kgcompared with control was less than 0.001, indicating a significantdifference. The t test p value of 12fb at 15 mg/kg compared with controlwas 0.08, suggesting that this dose was not effective. Comparing 12fb at45 mg/kg with DTIC at 60 mg/kg, which had a TGI of 51%, the t test pvalue was about 0.001, suggesting that 12fb had substantially betteractivity than did DTIC. For the control and 12fb 15 mg/kg treatmentgroups, average body weight increased slightly throughout the experimentperiod.

To further confirm ABIs' in vivo activity, A375 human melanoma xenograftmodel on SHO mice was used, and 12fb at 25 mg/kg was tested. DTIC at 60mg/kg was used as a positive control again. After 31 days of treatment(FIG. 24C), 12fb inhibited melanoma tumor growth (TGI value) by 69%,whereas DTIC inhibited growth by 52%. The t test p value of 12fbtreatment versus control was less than 0.001, suggesting that 12fbsignificantly inhibited melanoma tumor growth at 25 mg/kg. The t test pvalue of 12fb treatment versus DTIC was less than 0.05, suggesting againthat 12fb had better activity than did DTIC. Average body weight of allgroups increased slightly throughout the experiment period. Physicalactivities for the mice also looked normal, suggesting that 25 mg/kg wasa well tolerated dose for SHO mice.

Example 19 Binding to Colchicine Materials and Methods

Each test compound was prepared at 20× concentration in G-PEM buffer(Cytoskeleton Inc., Denver, Colo.) followed by pipetting 10 μL of testcompound into the 96-well plates. Ten microliters of tritiated labeledcolchicine (Perkin-Elmer, Waltham, Mass.) was added to each testingwell. Subsequently, 180 μL bead/tubulin (GE Healthcare Bio-SciencesCorp., Piscataway, N.J.) suspension was added into each well. The platewas incubated for 45 min at 37° C. before it was read by a Topcount NXTplate reader (Perkin-Elmer, Waltham, Mass.). Nonradiolabeled “cold”colchicine was included as a positive control and paclitaxel as anegative control because paclitaxel binds to a different site in tubulinand does not compete for the colchicine site binding. Data wereprocessed using GraphPad Prism software.

Cell Cycle Analysis

Flow cytometry analysis was performed to study cell cycle phasedistribution. A375 cells were cultured in 10-cm tissue culture dishesuntil the confluence was about 80%, and then cells were treated with 0,10, 50, 200, and 1000 nM of colchicine, 12da, 12fb and 12cb, for 24 h ingrowth media. Cellular DNA was stained with PBS containing 50 μg/mLpropidium iodide and 100 μg/mL RNase A. The cell cycle was determinedusing a BD LSR-II cytometer (BD Biosciences, San Jose, Calif.) with10,000 cells scored. Data were analyzed and graphs were prepared usingthe Modfit 2.0 program (Verity Software House, Topsham, Me.).

Results

Three ligand binding sites in tubulin α/β-heterodimer have beenreported: paclitaxel binding site, vinblastine binding site, andcolchicine binding site. The binding affinity of compound 12cb using³H-labeled colchicine and a competitive binding scintillation proximityassay (SPA) was measured. The results confirmed the strong binding of12cb with a binding affinity of 3.4±1.5 μM (FIG. 25A). Colchicine boundtubulin with an IC₅₀ value of 1.8±0.5 μM under these conditions. Theseresults clearly indicated that ABI compounds effectively inhibit tubulinpolymerization.

The binding graph (FIG. 25A) clearly shows that ABIs can competitivelybind to the tubulin colchicine binding site. As the concentration of thethree tested compounds increased from 0.03 M to 100 μM, increasedtritiated colchicine was competitively stripped away from tubulin, andemitted lower SPA counts. The negative control, paclitaxel, gave only aflat line, because theoretically it should not bind to the colchicinebinding site on tubulin. Second, ABIs have relatively high bindingaffinity to the tubulin colchicine binding site. GraphPad Prismcalculated IC₅₀ values for binding showed that 12da has the highestbinding affinity. The binding affinity was positively correlated to invitro antimelanoma activity; the higher the binding affinity, the higherthe antimelanoma activity.

ABIs demonstrated that they arrest cells by cell cycle analysis in theG2/M phase as indication that they target tubulin. Compounds 12da, 12fband 12cb were tested together with colchicine as a positive control onA375 cells (FIG. 25B). Four different concentrations—10, 50, 200, and1000 nM—of each compound were chosen to show the dose effect (FIGS. 25Cand 25D). For controls (no treatment) without interference, about 16% ofA375 cells were distributed in the G2/M phase. For the colchicinetreatment group, as concentration increased from 10 nM to 50 nM, thepercentage of cells distributed in the G2/M phase increased from 14% to85%. ABIs had similar results for A375 cells, in arresting them in theG2/M phase in a dose-dependent manner. The potency of the differentconcentrations in arresting cells in the G2/M phase positivelycorrelated with in vitro activity.

Example 20 In Vitro and In Vivo Pharmacology of Compounds 17ya, 12Fa,and 55 Materials and Methods

Cell culture and cytotoxicity assay of prostate cancer. All prostatecancer cell lines (LNCaP, PC-3, and DU145, PPC-1) were obtained fromATCC (American Type Culture Collection, Manassas, Va., USA). HumanPC-3_T×R, was resistant to paclitaxel and used a MDR model compared withPC-3. Cell culture supplies were purchased from Cellgro Mediatech(Herndon, Va., USA). All cell lines were used to test theantiproliferative activity of compounds 17ya, 12fa, and 55 bysulforhodamine B (SRB) assay. All cancer cell lines were maintained inRPMI 1640 media with 2 mM glutamine and 10% fetal bovine serum (FBS).

In vitro microtubule polymerization assay. Porcine brain tubulin (0.4mg) (Cytoskeleton, Denver, Colo.) was mixed with 1 and 5 μM of the testcompound or vehicle (DMSO) and incubated in 100 μl of buffer (80 mMPIPES, 2.0 mM MgCl₂, 0.5 mM EGTA, pH 6.9 and 1 mM GTP). The absorbanceat 340 nm wavelength was monitored every min for 15 min (SYNERGY 4Microplate Reader, Bio-Tek Instruments, Winooski, Vt.). Thespectrophotometer was maintained at 37° C. for tubulin polymerization.

Metabolic incubations. Metabolic stability studies were conducted byincubating 0.5 μM of test compounds in a total reaction volume of 1 mLcontaining 1 mg/mL microsomal protein in reaction buffer [0.2 M ofphosphate buffer solution (pH 7.4), 1.3 mM NADP⁺, 3.3 mMglucose-6-phosphate, and 0.4 U/mL glucose-6-phosphate dehydrogenase] at37° C. in a shaking water bath. The NADPH regenerating system (solutionA and B) was obtained from BD Biosciences (Bedford, Mass.). Forglucuronidation studies, 2 mM UDP-glucuronic acid (Sigma, St. Louis,Mo.) cofactor in deionized water was incubated with 8 mM MgCl₂, 25 μg ofalamethicin (Sigma, St. Louis, Mo.) in deionized water, and NADPHregenerating solutions (BD Biosciences, Bedford, Mass.) as describedpreviously. The total DMSO concentration in the reaction solution wasapproximately 0.5% (v/v). Aliquots (100 μL) from the reaction mixturesused to determine metabolic stability were sampled at 5, 10, 20, 30, 60,and 90 min. Acetonitrile (150 μL) containing 200 nM of the internalstandard was added to quench the reaction and to precipitate theproteins. Samples were then centrifuged at 4,000 g for 30 min at RT, andthe supernatant was analyzed directly by LC-MS/MS.

Analytical method. Sample solution (10 μL) was injected into an Agilentseries HPLC system (Agilent 1100 Series Agilent 1100 Chemstation,Agilent Technology Co, Ltd). All analytes were separated on anarrow-bore C18 column (Alltech Alltima HP, 2.1×100 mm, 3 μm, Fisher,Fair Lawn, N.J.). Two gradient modes were used. For metabolic stabilitystudies, gradient mode was used to achieve the separation of analytesusing mixtures of mobile phase A [ACN/H₂O (5%/95%, v/v) containing 0.1%formic acid] and mobile phase B [ACN/H₂O (95%/5%, v/v) containing 0.1%formic acid] at a flow rate of 300 μL/min. Mobile phase A was used at10% from 0 to 1 min followed by a linearly programmed gradient to 100%of mobile phase B within 4 min, 100% of mobile phase B was maintainedfor 0.5 min before a quick ramp to 10% mobile phase A. Mobile phase Awas continued for another 10 min towards the end of analysis.

A triple-quadruple mass spectrometer, API Qtrap 4000™ (AppliedBiosystems/MDS SCIEX, Concord, Ontario, Canada), operating with aTurboIonSpray source was used. The spraying needle voltage was set at 5kV for positive mode. Curtain gas was set at 10; Gas 1 and gas 2 wereset 50. Collision-Assisted-Dissociation (CAD) gas at medium and thesource heater probe temperature at 500° C. Multiple reaction monitoring(MRM) mode, scanning m/z 378→210 (17ya), m/z 373→205 (12fa), m/z 410→242(55) and m/z 309→171 (internal standard), was used to obtain the mostsensitive signals. Data acquisition and quantitative processing wereaccomplished using Analyst™ software, Ver. 1.4.1 (Applied Biosystems).

Aqueous solubility. The solubility of drugs was determined byMultiscreen Solubility Filter Plate (Millipore Corporate, Billerica,Mass.) coupled with LC-MS/MS. Briefly, 198 μL of phosphate bufferedsaline (PBS) buffer (pH 7.4) was loaded into 96-well plate, and 2 μL of10 mM test compounds (in DMSO) was dispensed and mixed with gentleshaking (200-300 rpm) for 1.5 hours at RT (N=3). The plate wascentrifuged at 800 g for 10 min, and the filtrate was used to determineits concentration and solubility of test compound by LC-MS/MS asdescribed previously.

Pharmacokinetic study. Male ICR mice (n=3 per group) 6 to 8 weeks of agewere purchased from Harlan Inc., and used to examine thepharmacokinetics (PK) of 17ya, 12fa, and 55. All compounds (10 mg/kg)were dissolved in DMSO/PEG300 (1/9) and administered by a singleintravenously (i.v.) injection (50 μL) into the tail vein. Blood sampleswere collected at 5, 15, and 30 min, 1, 1.5, 2, 3, 4, 8, 12, and 24 hrafter i.v. administration. Mice were given (p.o.) by oral gavage at 20mg/kg (in Tween80/DMSO/H₂O, 2/2/6) of each test compound to evaluatetheir oral bioavailability. Blood samples were collected at 0.5, 1, 1.5,2, 3, 4, 8, 12, and 24 hr after p.o. administration.

Female Sprague-Dawley rats (n=3; 254±4 g) were purchased from HarlanInc. (Indianapolis, Ind.). Rat thoracic jugular vein catheters werepurchased from Braintree Scientific Inc. (Braintree, Mass.). On arrivalat the animal facility, the animals were acclimated for 3 days in atemperature-controlled room (20-22° C.) with a 12-h light/dark cyclebefore any treatment. Compounds 17ya, 12fa, and 55 were administeredi.v. into the thoracic jugular vein at a dose of 5 mg/kg (inDMSO/PEG300, 1/9). An equal volume of heparinized saline was injected toreplace the removed blood, and blood samples (250 μl.) were collectedvia the jugular vein catheter at 10, 20, 30 min, and 1, 2, 4, 8, 12, 24hr. Rats were given (p.o.) by oral gavage at 10 mg/kg (inTween80/DMSO/H₂O, 2/2/6) of each test compound to evaluate their oralbioavailability. All blood samples (250 μL) after oral administrationwere collected via the jugular vein catheter at 30, 60, 90 min, 120 min,150 min, 180 min, 210 min, 240 min, and 8, 12, 24 hr. Heparinizedsyringes and vials were prepared prior to blood collection. Plasmasamples were prepared by centrifuging the blood samples at 8,000 g for 5min. All plasma samples were stored immediately at −80° C. untilanalyzed.

Analytes were extracted from 100 μL of plasma with 200 μL ofacetonitrile containing 200 nM the internal standard. The samples werethoroughly mixed, centrifuged, and the organic extract was transferredto autosampler for LC-MS/MS analysis.

PC-3_T×R xenograft studies. PC-3_T×R cells (10×10⁷ per mL) were preparedin RPMI1640 growth media containing 10% FBS, and mixed with Matrigel (BDBiosciences, San Jose, Calif.) at 1:1 ratio. Tumors were established byinjecting 100 μL of the mixture (5×10⁶ cells per animal) subcutaneously(s.c.) into the flank of 6-8-week-old male athymic nude mice. Length andwidth of tumors were measured and the tumor volume (mm³) was calculatedby the formula, π/6×L×W², where length (L) and width (W) were determinedin mm. When the tumor volumes reached 300 mm³, the animals bearingPC-3_T×R tumors were treated with vehicle [Tween80/DMSO/H₂O (2/2/6)], or17ya (10 mg/kg) orally. The dosing schedule was 3 times a week for fourweeks.

Results

TABLE 15 In vitro efficacy of 17ya, 12fa, and 55 on prostate (PC-3) anddrug resistant (PC-3_TxR) cell lines (n = 3, mean ± SE). Paciltaxel wasused as positive controls IC₅₀ ± SEM (nM) Cell line Cell type 17ya 12fa55 Paclitaxel LNCaP Prostate 12 ± 1   24 ± 1   27 ± 0.6 1.7 ± 0.2 PC-3Prostate 10 ± 0.4 35 ± 1   28 ± 1   4.8 ± 0.3 Du-145 Prostate 17 ± 0.236 ± 0.4 38 ± 0.6 5.1 ± 0.1 PPC-1 Prostate 21 ± 0.1 26 ± 0.2 36 ± 0.42.3 ± 0.8 PC-3 Prostate 5.6 ± 0.1  NA 24 ± 0.3 4.8 ± 0.3 PC-3_TxRProstate 6.7 ± 0.2  NA 29 ± 1   97 ± 1  Resistance 1.2 NA 1.2 20 Factor

Compounds 17ya and 55 inhibit the growth of multidrug-resistant cancercell lines. The ability of 17ya and 55 to inhibit the growth of cancercell lines was evaluated using the SRB assay. As shown in Table 15, both17ya and 55 inhibited the growth of four prostate cancer cell lines,with IC₅₀ values in the low nanomolar range. These data suggested thatboth compounds exhibited comparable cytotoxicity with paclitaxel. Inaddition, the effect of 17ya and 55 in the PC-3 and PC-3_T×R cell lineswas also evaluated (Table 15). Both 17ya and 55 were equally potentagainst MDR cell (PC-3_T×R) and the parent cell line (PC-3). Paclitaxelexhibited relative resistance values of 20 times. These data indicatethat the 17ya and 55 circumvent P-gp-mediated drug resistance.

17ya and 55 Inhibit Microtubule Polymerization.

Porcine brain tubulin (>97% pure) was incubated with the individualcompounds 17ya and 55 (1 and 5 μM) to test their effect on tubulinpolymerization (FIG. 26). Compound 17ya inhibited tubulin polymerizationby 13 and 47% at 1 and 5 μM, respectively. Compound 55 inhibited tubulinpolymerization by 11 and 40% at 1 and 5 μM, respectively. 5 μM ofcolchicine was used as a positive control and exhibited 32% inhibitionon tubulin polymerization. These data suggested that both 17ya and 55had slightly greater inhibition on tubulin polymerization thancolchicine and inhibited in a dose dependent manner.

Compound 17ya is Stable in Human Liver Microsomes. Compound 12fa and 55Show Acceptable Metabolic Stability

TABLE16 Summary of drug-like and pharmacokinetic properties of 17ya,12fa, 55, and 1h.

Molecular weight 377 372 IC₅₀ in PC3 (nM) nM 10 35 Half-life in HLM(Phase I) min ~80 44 Half-life in HLM (Phase I + II) min ~90 NASolubility μg /mL >75 12 RatPK_IV5mgk_Cl mL/min/kg 9.5 16 RatPK_IV5mgk_VLkg 1.8 1.9 RatPK_PO10mgk_Cmax ng/mL 831 1109 RatPK_PO10mgk_AUCmin*μg/mL 235 218 RatPK_Bioavailability %F 21 35 MousePK_IV10mgk_ClmLmin/kg 19 61 MousePK_IV10mgk_V Lkg 2.9 4 MousePK_PO20mgk_Cmax ng/mL1560 2592 MousePK_PO20mgk_AUC min*μg /mL 384 201 MousePK_Bioavailability%F 36 62

Molecular weight 409 355 IC₅₀ in PC3 (nM) nM 28 21 Half-life in HLM(Phase I) min 30 17 Half-life in HLM (Phase I + II) min 43 17 Solubilityμg /mL 19 1 RatPK_IV5mgk_Cl mL/min/kg 10 7.7 (2.5 mpk) RatPK_IV5mgk_VLkg 1.0 4.9 (2.5 mpk) RatPK_PO10mgk_Cmax ng/mL 1052 212RatPK_PO10mgk_AUC min*μg/mL 335 37 RatPK_Bioavailability %F 33 3.3MousePK_IV10mgk_Cl mLmin/kg 40 130 MousePK_IV10mgk_V Lkg 1.3 4.9MousePK_PO20mgk_Cmax ng/mL 1253 NA MousePK_PO20mgk_AUC min*μg /mL 171 NAMousePK_Bioavailability % F 34 NA

As shown in Table 16, 17ya had a half-life of 80 min by phase Ireaction, suggesting that 17ya was stable in phase I metabolicprocesses. The half-life (90 min) in the presence of UDP-glucuronic acidwas similar to that observed in its absence. These data suggested that17ya is stable in human liver microsomes, and it was hoped that lowclearance and long half-life will be obtained in human. On the otherhand, 55 exhibited 30 and 43 min as half lives when it was in thepresence and absence of UDP-glucuronic acid, respectively. Compound 12fashows the half-life with 44 in phase I. These data suggested that allthree compounds showed acceptable stability in human liver microsomes,and 17ya is more stable than 12fa and 55. When investigating theirmetabolism, it was found that 12fa and 55 exhibited higher levels ofketone-reduction (data not shown), suggesting that 12fa and 55 are morelabile than 17ya.

Compound 17ya Exhibited Great Aqueous Solubility, 12fa and 55 ShowedAcceptable Solubility.

Compound 17ya contained an imidazole ring, and this ring improvedaqueous solubility, resulting in >75 μg/mL aqueous solubility (Table16). Compounds 12fa and 55 exhibited less aqueous solubility, andexhibited 12 and 19 μg/mL, respectively. Overall, 17ya demonstrated agreat aqueous solubility, and 12fa and 55 showed acceptable aqueoussolubility, and much improved over 1h.

All compounds 17ya, 12fa and 55 Showed Great Pharmacokinetic Propertiesand Bioavailability in Mice and Rats.

A single dose IV bolus of 17ya, 12fa, and 55 was administered to ICRmice, and Sprague-Dawley rats. Their PK parameters are summarized inTable 16. In vivo total clearances were 19, 61 and 40 mL/min/kg for17ya, 12fa, and 55 in mice, respectively. In rats, their in vivo totalclearances were 9.5, 16 and 10 mL/min/kg for 17ya, 12fa, and 55respectively. Compound 17ya exhibited low clearance in both mice andrats. Compounds 12fa and 55 also had a low clearance in rats, but amoderate clearance in mice. These clearance values suggested that allcompounds may overcome first-pass metabolism and exhibit a great chanceto be orally bioavailable agents. Intermediate volumes of distributionof 2.9 and 1.8 L/kg were obtained from 17ya; 4 and 1.9 L/kg wereobtained from 12fa, 1.3 and 1.0 L/kg were obtained from 55 in mouse andrat, respectively. The oral bioavailability was 36% and 21% from 17ya inmice and rats. On the other hand, 12fa had 62% and 35% oralbioavailability, 55 exhibited 34% and 33% oral bioavailability in miceand rats, respectively. These data suggested that all compounds 17ya,12fa, and 55 may be potentially used orally.

Compound 17ya Inhibits Paclitaxel Resistant Prostate Xenografts Growth.

Paclitaxel resistant prostate cancer PC-3_T×R tumors in mice wereallowed to reach a volume of 300 mm³ and then tumor-bearing mice weretreated with 10 mg/kg of 17ya orally. As shown in FIG. 27, tumor volumesin the control group increased to 1521±35 mm³ (mean±SE) over 13 days.Mice in vehicle group lost>20% body weight and were sacrificed onday-13. Tumor volumes in the 17ya-treated group slightly increasedbefore day 6. However, their tumor sizes were reduced below theiroriginal tumor sizes, suggesting that partial regression was obtained bythe treatment group. In addition, their body weights increased overtime, suggesting the treatment did not show apparent toxicity.

Example 21 Pharmacokinetics of Compounds of this Invention

TABLE 17 Half life in Half life in Half life in Half life in Half lifein Human liver Mouse liver Rat liver Dog liver Monkey liver Compoundmicrosome microsome microsome microsome microsome ID (min) (min) (min)(min) (min)  1h 17 <5 31 19 <5  2e-cis 35  2i 32  2k 10 9 32 16 <5  2l20 11 49 30 8  6a 32 3.43 12 13 16  6b 40 10 9 30 13  6c 47 13 14 29 9 7d 24 37 42 29 15 12da 23 8 28 17 12fa 56 23 46 26 12fb 37 12dab 21 <512 46

Example 22 Biological Activity of 4-Substituted Methoxybenzoyl-ArylThiazole (Smart): an Active Microtubule Inhibitor Materials and Methods

In vitro microtubule polymerization assay. Bovine brain tubulin (0.4 mg)(Cytoskeleton, Denver, Colo.) was mixed with 10 μM of the test compoundor vehicle (DMSO) and incubated in 100 μl of buffer (80 mM PIPES, 2.0 mMMgCl2, 0.5 mM EGTA, pH 6.9 and 1 mM GTP). The absorbance at 340 nmwavelength was monitored every min for 15 min (SYNERGY 4 MicroplateReader, Bio-Tek Instruments, Winooski, Vt.). The spectrophotometer wasmaintained at 37° C. for tubulin polymerization.

MS competition binding assay. Colchicine, vinblastine, and paclitaxel(1.2 μM for each) were incubated with tubulin (1.2 mg/mL) in theincubation buffer (80 mM PIPES, 2.0 mM MgCl₂, 0.5 mM EGTA, pH 6.9) at37° C. for 1 hr. 1h (0.5-125 μM) was examined to individually competewith colchicine-, vinblastine-, and paclitaxel-tubulin binding. Thefree-form ligands were separated from tubulin or microtubule using anultrafiltration method (microconcentrator) (Microcon, Bedford, Mass.)with a molecular cutoff size of 30k Da. Colchicine, vinblastine andpaclitaxel were determined by LCMS/MS method. The ability of 1h toinhibit the binding of ligands was expressed as a percentage of controlbinding in the absence of any competitor. Each reaction was run intriplicate.

Cell culture and cytotoxicity assay of prostate and melanoma cancer. Allprostate and melanoma cell lines were obtained from ATCC (American TypeCulture Collection, Manassas, Va., USA), while cell culture supplieswere purchased from Cellgro Mediatech(Herndon, Va., USA). Theantiproliferative activity of the compounds was examined in four humanprostate cancer cell lines (LNCaP, DU 145, PC-3, and PPC-1) and twohuman melanoma cell lines (A375 and WM-164). Human ovarian cell lineOVCAR-8 and its resistant cell line that over-expresses P-gp,NCI/ADR-RES, were used as MDR models. Both ovarian cell lines wereobtained from National Cancer Institutes (NCI). All prostate cancer celllines were cultured with 10% fetal bovine serum (PBS).

Cell cycle analysis. Flow cytometry was performed to study the effectsof the compounds on cell cycle distribution. PC-3 and A375 cells weretreated in growth media with the indicated concentrations of compounds1h, 2k, 21 for 24 h. Cellular DNA was stained with 100 μg/mL propidiumiodide and 100 μg/mL RNase A in PBS and flow cytometry was performed todetermine the cell cycle distribution of the cells.

Apoptosis detection by ELISA. Quantification of the enrichment of mono-and oligonucleosomes in the cytoplasm was used to determine the abilityof the compounds to induce apoptosis (cell death detection ELISA PLUS,Roche, Germany) following the manufacturer's instructions.

Pharmacokinetic study. Male ICR mice (n=3 or 4 per group) 6 to 8 weeksof age were purchased from Harlan Inc., and used to examine thepharmacokinetics (PK) of the compounds. 1h, 2k, 2l (15 mg/kg) weredissolved in PEG300/DMSO (1/4) and administered by a single i.v.injection into the tail vein. Blood samples were collected at 2, 5, 15,and 30 min, 1, 2, 4, 8, 16, and 24 hr after administration. MaleSprague-Dawley rats (n=4; 254±4 g) were purchased from Harlan Inc.(Indianapolis, Ind.). 1h, 2k, were administered intravenously into thejugular venous catheters at 2.5 mg/kg (in DMSO/PEG300, 1/4). Bloodsamples (250 μL) were collected at 10, 20, 30 min, and 1, 2, 4, 8, 12,24, 48 h. A protein precipitation method was used for samplepreparation. An aliquot (200 μL) of acetonitrile (ACN) was added to 100μL of plasma and then was thoroughly vortexed for 15 s. Aftercentrifugation, the supernatant was analyzed by liquid chromatographytandem mass spectrometry (LC-MS/MS). The PK parameters were determinedusing Non compartment analysis (WinNonlin, Pharsight Corporation,Mountain View, Calif.).

PC-3 and A375 tumor xenograft studies. PC-3 and A375 cells (5×10⁷ permL) were prepared in phenol red-free growth media containing 10% FBS,and mixed with Matrigel (BD Biosciences, San Jose, Calif.) at 1:1 ratio.Tumors were established by injecting 100 μL of the mixture (2.5×10⁶cells per animal) subcutaneously (s.c.) into the flank of 6-8-week-oldmale athymic nude mice. Length and width of tumors were measured and thetumor volume (mm³) was calculated by the formula, π/6×L×W², where length(L) and width (W) were determined in mm. When the tumor volumes reached150 mm³, the animals bearing PC-3 tumors were treated with vehicle[Captex200/Tween80 (1/4)], 1h (5 and 15 mg/kg), 2k (5 and 15 mg/kg) and21 (50 mg/kg) intraperitorally for 21 days. Vinblastine (0.5 mg/kg) wasused as the positive control and dosed q2d with vehicle [DMSO/PEG300(1/9)]. On the other hand, A375 tumor bearing mice were treated for 34days with vehicle [Captex200/Tween80 (1/4)], 1h (20 mg/kg) or 2k (15mg/kg). Doses were selected based on acute toxicity studies of 1h and 2kin ICR mice (n=2/group) showing that doses up to 30 mg/kg and 15 mg/kg,respectively, did not cause greater than 10% loss of body weight after 4consecutive days of intraperitoneal dosing.

In vivo antitumor activity [tumor growth inhibition (% T/C), tumorgrowth delay (T-C value), and tumor cell kill (total log cell kill)].Evidence of drug effect is described by the following parameters: %T/C=[Δ tumor volume of treated group]/[Δ tumor volume of controlgroup]×100%. The T-C values (tumor growth delay) were based on themedian time (in days), required for the treatment (T) and the controlgroup (C) tumors, to reach a predetermined size (600 mm³ in this study).These values were then used for the quantitation of the tumor cell killfollowing the equation: log cell kill=(T-C)/(3.32×Td). Td is the tumorvolume-doubling time in days. In this study, we defined the doublingtime required for the tumor to increase from 300 to 600 mm³.

Rotarod test. ICR mice received training three times a day for two daysto enable them to stay on the rotating rod for >120 seconds at 12 rpm.Mice were then randomized by the length of time that they could stay onthe rotating rod and divided into 7-8 mice per group. 1h at a dose of 5or 15 mg/kg in Captex200/Tween80 (1/4) was administered byintraperitoneal injection. Vinblastine at a dose of 0.5 mg/kg/day wasused as a positive control under the same conditions. The rotarod testwas performed twice a week. Treatment was stopped on day 31, and postobservation was examined on weeks 1, 2, and 4 after termination of thetreatment. The rod speed was increased from 59 rpm to 40 rpm over aperiod of 5 min. Performance was measured as the length of time that amouse could stay on the rotating rod.

In vivo drug resistance studies. At the end of the PC-3 xenograftstudies, solid tumors from control and 1h treated (15 mg/kg) groups wereremoved and digested with 0.1% collagenase (Type I) and 50 mg/mL DNAse(Worthington Biochemical Corp., Freehold, N.J.). Dispersed cells wereplated in RPMI medium+10% FBS and incubated at 37° C. and 5% CO₂ for 24hr to allow attachment. The anti-proliferative effects of 1h werecompared to determine whether tumor cells remaining in PC-3 xenograftsretained sensitivity to drug. The PC-3 cells obtained from ATCC wereused as in vitro control. Statistical analyses were performed usingsimple t-Test.

Results

Based on structure-activity relationship studies, three compounds (FIG.28A) were selected for biological characterization. While 1h and 2k arehighly potent molecules with low nanomolar cytotoxic properties, 2l,which was rationally designed as a potential metabolite with improvedsolubility, had the least potent anti-proliferative effects (Table 18).

TABLE 18 In vitro efficacy of compounds on prostate, melanoma and drugresistant cell lines (n = 3, mean ± SE). Paciltaxel, vinblastine, andcolchicine were used as positive controls a Previously reported inreference. IC₅₀ ± SEM (nm) Cell line Cell type SMART-H SMART-F SMART-OHPaclitaxel Vinblastine Colchicine LNCaP Prostate 28 ± 4^(a)  6 ± 1^(a)103 ± 9  1.7 ± 0.2 1.1 ± 0.1 16 ± 4 PC-3 Prostate 21 ± 1^(a) 13 ± 1^(a)87 ± 5 4.8 ± 0.3 2.1 ± 0.2 11 ± 1 Dn-145 Prostate 71 ± 4^(a) 12 ± 1^(a)116 ± 14 5.1 ± 0.1 1.8 ± 1.1 10 ± 2 PPC-1 Prostate 43 ± 5^(a)  8 ± 1^(a)76 ± 2 2.3 ± 0.8 1.1 ± 0.4 20 ± 1 B16-F1 Melanoma 55 ± 5^(a) 43 ± 21^(a)113 ± 6  17 ± 2  4.7 ± 0.7 29 ± 5 A375 Melanoma 28 ± 5^(a) 33 ± 14^(a) 93 ± 11 12 ± 3  1.1 ± 0.2 20 ± 3 OVCAR-8 Ovarian 35 ± 2 34 ± 3 110 ± 8 4.7 ± 0.1 3.9 ± 0.1 17 ± 1 NCI/ADR-RES Ovarian 13 ± 1 12 ± 1 45 ± 5 6263± 634  582 ± 57  1113 ± 79  Resistance Factor 0.4 0.4 0.4 1333 149 65SMART-H in Table 18 is 1h; SMART-F in Table 18 is 2k; and SMART-OH inTable 18 is 2l.

SMARTs Inhibit Microtubule Polymerization by Binding to the ColchicineBinding Site on Tubulin

Bovine brain tubulin (>97% pure) was incubated with the individualcompounds (10 μM) to test their effect on tubulin polymerization (FIG.28B). While 1h and 2k inhibited tubulin polymerization by 90%, 2linhibited the polymerization by only 55%. Previous studies demonstrateda concentration-dependent inhibition of tubulin polymerization by 1h. Inaddition, under the same experimental conditions, the IC₅₀ for 1h (4.23μM) is similar to that of colchicine (4.91 μM). These data suggest thatthe compounds exhibit strong antitubulin polymerization activity thatcorresponds well with their cytotoxicity (Table 18). The ability of thecompounds to compete for known binding sites on tubulin was determinedusing a novel MS competitive binding assay, which was developed in ourlaboratory. Three tubulin ligands, corresponding to the three bindingsites on tubulin, colchicine, vinblastine, and paclitaxel were used forthese competitive binding studies. It was found that, over aconcentration range of 0.1-125 μM, 1h specifically competed withcolchicine binding to tubulin, but it did not compete with eithervinblastine or paclitaxel binding to tubulin (FIG. 28C).

SMART Compounds Inhibit the Growth of Multidrug-Resistant Cancer CellLines

The ability of the compounds to inhibit the growth of cancer cell lineswas evaluated using the SRB assay. As shown in Table 18, the compoundsinhibited the growth of several human cancer cell lines, including fourprostate cancer cell lines, and two melanoma cell lines, with IC₅₀values in the low nanomolar range. Out of the three compounds, 2l wasthe least potent (IC₅₀ 76˜116 nM). 2k exhibited the bestanti-proliferative effect with IC₅₀ values between 6 and 43 nM inprostate cancer and melanoma cell lines. In addition, the effect of thecompounds in the OVCAR-8 and NCI/ADR-RES cell lines was also evaluated(Table 18). The compounds were equally potent against MDR cell(NCI-ADR-RES) and the parent cell line (OVCAR-8). Paclitaxel,vinblastine, and colchicine exhibited relative resistance values of1333, 149, and 65 times, respectively (Table 18). These data indicatethat the compounds circumvent P-gp-mediated drug resistance.

SMART compounds arrest PC-3 (Prostate) and A375 (Melanoma) cells in G2/Mphase of cell cycle and induce cell apoptosis. PC-3 and A375 cells wereexposed to 10, 50, 200, and 1000 nM of the compounds for 24 h. Treatmentwith the SMART compounds resulted in concentration-dependentaccumulation of both PC-3 and A375 cells in the G2/M phase withconcomitant decreases in the percentage of cells in G0/G1 phase (FIGS.29A and 29B). The proportion of cells in G2/M phase significantlyincreased when treated with 50 to 200 nM of 1h, 2k, 2l. Apoptosis wasthen examined by measuring the level of cytoplasmic DNA-histonecomplexes in PC-3 and A375 cells after 24 h treatment. Increasingconcentration of the SMART compounds increased the level of cytoplasmicDNA-histone complexes in PC-3 and A375 cells (FIG. 29C). The effect wasmore pronounced in A375 cells than PC-3 cells, but apoptosis was evidentin both cell types. 1h and 2k induced moderate apoptosis at aconcentration of 50 nM, while 2l induced apoptosis only atconcentrations greater than or equal to 200 nM.

In vivo PK profile of SMART compounds. A single dose bolus of eachcompound (15 mg/kg) was administered by tail vein injection to ICR miceto characterize their pharmacokinetics (FIG. 30A). 1h and 2k exhibitedsimilar PK properties, but 21 exhibited slightly greater AUC than 1h and2k indicative of a lower clearance for 21 (Table 19). 2l also had 2-3times higher V_(ss) than that of 1h and 2k. The clearance values for allthree compounds were equal to or higher than 90 mL/min/kg, the hepaticblood flow rate in mice, suggesting that in addition to hepatic removal,other degradation routes may be involved in the elimination of thecompounds. The pharmacokinetics of 1h and 2k (2.5 mg/kg) were alsoexamined in rats (FIG. 30B). Interestingly, low clearance values andhepatic extraction rates were obtained by both compounds, suggestingthat these compounds exhibit species differences in clearance. In rats,1h exhibited favorable pharmacokinetic properties, which are lowclearance (6 mL/min/kg), moderate volume of distribution (7.6 L/kg),long half-life (24 hr), and high exposure (AUC, 5.8 hr*μg/mL) (Table 19)when administered iv.

TABLE 19 Pharmacokinetic parameters of SMART compounds. SMARTs wereadministrated 15 mg/kg and 2.5 mg/kg i.v. in mice and rats,respectively. In vivo, pharmacokinetic parameters of SMART compoundsSMART- Species Parameter Unit H SMART-F SMART-OH Mice AUC hr * μg/mL 1.92.2 2.6 t_(1/2) min 140 141 740 V_(ss) L/kg 4.9 6.6 16.5 CL mL/min/kg130 112 90 Rats AUC hr * μg/mL 5.8 1.6 NA t_(1/2) min 1431 2410 NAV_(ss) L/kg 7.6 34 NA CL mL/min/kg 6 11 NA NA, not available SMART-H inTable 19 is 1h; SMART-F in Table 19 is 2k; and SMART-OH in Table 19 is2l.

SMART compounds inhibit prostate and melanoma xenografts growth withoutneurotoxicity. Prostate cancer PC-3 and melanoma A375 tumors in micewere allowed to reach a volume of 150 mm³ and then tumor-bearing micewere treated with the SMART compounds. As shown in FIG. 31A, tumorvolumes in the control group increased to 680 mm³ over the 21 dayduration of the study. Tumor volumes in the 1h treated group increasedto 370 mm³ (5 mg/kg treatment) and 176 mm³ (15 mg/kg treatment) by day21, indicating strong anti-tumor activity for this compound. Tumors inthe 2k-treated animals increased to 269 mm³ (5 mg/kg treatment) and 292mm³ (15 mg/kg treatment), while animals in the 2l (50 mg/kg) treatedgroup had tumors of 331 mm³ at day 21. This reduction in tumor volumereversed upon withdrawal of SMART compounds (data not shown). Table 20summarized the in vivo efficacy (% T/C, T-C values, and log cell kill)of SMART compounds.

TABLE 20 In vivo efficacy of SMART compounds (administered i.p.) onprostate (PC-3), melanoma (A375). % T/C, T-C value, and log cell killare summarized. The doubling time of melanoma xenograft was 4.6 d.Vinblastine was used as the positive control. % T/C ≦ 42% is consideredto be moderately active by National Cancer Institute criteria. Mediantime to Total Dosage Xenograft % reach T − C log Compound (mg/kg) modelT/C 600 mm³ (days) cell kill Vehicle NA Prostate 100 19 days NA NAVinblastine 0.5 Prostate 29 NA NA NA SMART-H 5 Prostate 29 NA NA NASMART-H 15 Prostate 4 NA NA NA SMART-F 5 Prostate 21 NA NA NA SMART-F 15Prostate 24 NA NA NA SMART-OH 50 Prostate 34 NA NA NA Vehicle NAMelanoma 100 18 days NA NA SMART-H 20 Melanoma 30 28 days 10 0.7 SMART-F15 Melanoma 28 29 days 11 0.7 NA, not available. SMART-H in Table 20 is1h; SMART-F in Table 20 is 2k; and SMART-OH in Table 20 is 2l.

1h tumor elicited % T/C=29% and 4% at 5 and 15 mg/kg treatment (alldoses were intraperitoneal (i.p.)), respectively, whereas, 2k elicited %T/C of 21% and 24% at 5 and 15 mg/kg treatment, respectively. The highdose of 2l (50 mg/kg) exhibited the % T/C of 34%. Vinblastine, thepositive control, showed % T/C of 29% at day 22 in PC-3 xenografts (FIG.31B). Body weight measurements, to monitor toxicity, indicated that only1 of 8 mice treated with 1h (15 mg/kg), and 2 out of 7 mice treated with2k (15 mg/kg) lost more than 15% body weight. In addition to theantitumor effects of the compounds on PC-3 prostate tumors, 1h (20mg/kg) and 2k (15 mg/kg) demonstrated a significant reduction of A375tumors. As shown in FIG. 31C, the tumor volumes of control groupincreased to 2183 mm³, whereas the 14 volumes in 1h and 2k treatmentgroups increased to 775 mm³ and 722 mm³, respectively. 1h and 2ktreatment evoked % T/C of 28% and 29%, respectively. Rotarod tests wereperformed to examine the in vivo neurotoxic effects of 1h. Based on theresult of in vivo efficacy experiments, 5 or 15 mg/kg [i.p.administration, Captex200/Tween80 (1/4)] of 1h was chosen to study theeffect on motor coordination. A 0.5 mg/kg treatment with vinblastine wasused as the positive control under the same conditions. As shown in FIG.31D, vinblastine gradually reduced the time (in seconds) that the micecould stay on the rotating rod, and attained significance by days 27 and31 (p<0.05) compared to the vehicle group. However, no significantdifference was observed in the 1h treatment groups, suggesting that 1hdid not cause neurotoxicity in ICR mice at doses that are associatedwith antitumor effects.

1h did not develop drug-resistance in PC-3 tumor bearing mice. Weexcised the PC-3 tumors from nude mice after 21 days of treatment withvehicle (n=3) or 15 mg/kg 1h (n=3). Solid tumors were digested anddispersed into cells as described in the methods section. PC-3 cell linefrom ATCC (American Type Culture Collection, Manassas, Va., USA) wasused as a control. IC₅₀ values were 29.1±1.1, 29.1±0.8, and 30.4±0.5 nMin PC-3 cells from ATCC, and dissociated cells from vehicle and 1htreated tumors, respectively. These data demonstrate that 1h did notinduce drug-resistance in PC-3 tumors after 21 days of continuous 1htreatment.

Example 23 Molecular Modeling Methods

All molecular modeling studies were performed with Schrodinger MolecularModeling Suite 2008 (Schrodinger LLC, New York, N.Y.), running on a DellLinux workstation. Because the size of ABI compounds are much closer tothat of ABT-751, rather than DAMA-colchichine, we selected tubulincomplex with ABT-751 (PDB code: 3 KHC) as our modeling system. ABIs werebuilt and prepared using the Ligprep module, and they were docked intothe ABT-751 site using the Glide module in Schrodinger Suite. The bestdocking complexes were subject to restricted molecular dynamics torelease any strains using Macromodel module with OPLS-2005 forcefield.The ligand and its surrounding residues within 15 Å were allowed to movefreely, while residues outside the 15 Å radius were kept rigid.

Results

Molecular modeling for binding ABI compounds in tubulin was studied.Several crystal structures of the ligand-tubulin complex are availablein the PDB databank, with the most recent one from Dorleans et al. Ingeneral, the colchicine binding pocket tolerates a variety of molecularstructures, which may indicate substantial conformation changes uponligand binding. In fact, Dorleans et al. solved the crystal structuresof both the empty tubulin dimer and the ligand-tubulin complex. Theyfound that, without the presence of ligand, loop 7 (T7, residues244-251, FIG. 32) in the beta-monomer folds in to occupy the bindingpocket, while it flips out upon ligand binding. The associated helix 7(H7, residues 224-243) and helix 8 (H8, residues 252-260) were displacedupon ligand binding. It is conceivable that the extent to which 17 isdisplaced depends on the size of individual ligand. This flexibilitypresents a significant challenge to understand the precise binding modesfor individual ligands without solving actual crystal structures.Nevertheless, careful analysis of the possible binding modes couldprovide some insights into the binding of different ligands.

The binding modes of 12cb and 11cb (stick model) are shown in FIGS. 32Aand 32B. For comparison, the crystal structure complexes of ABT-751 andDAMA-colchicine (wire models) along with ABI-12cb/tubulin complex inFIG. 32A is displayed. For clarity, only the related secondarystructures forming the binding pocket in 13-tubulin are shown in FIG.32A. The overall structures of 12cb, ABT-751 and DAMA-colchicineoverlapped very well in the binding pocket. Several potential hydrogenbonding interactions between compound 12cb and tubulin were identified.The carbonyl group in 12cb was in sufficient proximity to form twohydrogen bond interactions with the backbone NH of Leu-252 in H8 and thesidechain of Asp-251 in 17 of the tubulin β-monomer. The para-fluorinesubstituent in the C-ring was close to the sidechain of Cys241 in T7 andTyr202 in S6, possibly forming one or two hydrogen bonds. The imidazoleproton is very close and likely to form a hydrogen bond to Thr179 in T5loop (residues 173-182) of the tubulin α-monomer (FIG. 32A). Togetherwith the hydrophobic interactions provided by the aromatic rings, thelikely formation of these hydrogen bonds would contribute to the highbinding affinity to the tubulin dimer, resulting in highantiproliferative potency.

The binding mode of 11cb will be conceivably less defined since two ofthe three aromatic rings may occupy the binding pocket in the β-monomerwhile the third ring may extend toward the interface of theα/β-monomers, similar to how the sidechain of DAMA-chochicine binds. Ourmodeling indicates that the protecting group likely extends to thetubulin dimer interface, while the A, C rings of 11cb occupy similarbinding pocket and orientation as 12cb (FIG. 32B). This may explain thesimilar activity between the two compounds, even though 11cb has anextra ring system. From the molecular modeling studies presented inFIGS. 32A and 32B, the hydrogen bond donor is likely to be the thiolgroup in Cys-241 in loop 7 of the β-subunit in α/β-tubulin dimer.

The binding mode of ABI 12fb was modeled (not shown) and compared toDAMA-colchicine (see FIG. 19 for structure of colchicine) in theα/β-tubulin heterodimer. The overall structure of 12fb andDAMA-cochicine overlapped very well. The p-fluoro phenyl moiety overlapswith the trimethoxylpheny moiety which is interacting with the T7 loopin the β-subunit. Similarly, the p-chloro phenyl moiety occupies theother side of the pocket where the seven-member ring of theDAMA-cochicine is, with the chlorine atom occupying the pocket where themethoxy moiety interacts.

Example 24 Microtobule Imaging Materials and Methods

Cellomics Cytoskeleton rearrangement kit (Thermo Scientific, Rockford,Ill.) was used to get a visually appreciable proof of ABIs interactingwith tubulin inside the cells. WM-164 melanoma cells were treated witheach compound for 18 h in duplicate using a collagen-coated 96-wellplate (Becton Dickinson Labware, Bedford, Mass.). Then cells were fixedwith 4% paraformaldehyde (Thermo Scientific, Rockford, Ill.) andpermeabilized using permeabilization buffer supply from the kit. Primaryantibody for tubulin and fluorescence-labeled secondary antibody weresubsequently added to the cells. Cell nuclei were stained by DAPI. WholeCell Stain Green was also applied to all cells. All images were acquiredwith an Olympus IX71 inverted fluorescence microscope (Olympus Corp.,Tokyo, Japan) with overlays from separate

images of tubulin (red), nuclei (blue), and whole cells (green). Forcomparison, paclitacel, colchicine and ABT-751, along with ABIs areincluded.

Results

Visual proof of ABIs interacting with tubulin inside the cells wasexamined. The microtubule arrangement in human melanoma WM-164 cellsupon treatment with different compounds is presented in FIG. 33. Themicrotubule images clearly showed that all five tested compoundsresulted in cytoskeleton rearrangement. There was a significantdifference between paclitaxel and the other four compounds (colchicine,ABT-751, 12cb, and 12da). Treatment with paclitaxel resulted in acondensation of microtubules orderly lying around the nuclei comparedwith controls, consistent with its mechanisms of action for stabilizingmicrotubules. On the contrary, treatment with colchicine, ABT-751, 12cb,and 12da had similar effects on microtubules and resulted in some degreeof microtubule fragmentation, consistent with their common mechanism ofaction for destabilizing microtubules. These results also confirmed thatABIs shared the same cellular target with colchicine and induced thesame cellular effect.

All of the features described herein (including any accompanying claims,abstract and drawings), and/or all of the steps of any method or processso disclosed, may be combined with any of the above aspects in anycombination, except combinations where at least some of such featuresand/or steps are mutually exclusive. Although preferred embodiments havebeen depicted and described in detail herein, it will be apparent tothose skilled in the relevant art that various modifications, additions,substitutions, and the like can be made without departing from thespirit of the invention and these are therefore considered to be withinthe scope of the invention as defined in the claims which follow.

1. A compound represented by the structure of formula (Ia):

A is substituted or unsubstituted single-, fused- or multiple-ring, arylor (hetero)cyclic ring systems; substituted or unsubstituted, saturatedor unsaturated N-heterocycles; substituted or unsubstituted, saturatedor unsaturated S-heterocycles; substituted or unsubstituted, saturatedor unsaturated O-heterocycles; substituted or unsubstituted, saturatedor unsaturated cyclic hydrocarbons; or substituted or unsubstituted,saturated or unsaturated mixed heterocycles; B is

R₁, R₂ and R₃ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl,Br, I, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂,—(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branched alkyl, haloalkyl,alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph,C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂; R₁₀ and R₁₁ are independentlyhydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, CF₃, CN, —CH₂CN, NH₂,hydroxyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃,C₁-C₅ linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl,—OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ orNO₂; X is a bond, NH, C₁ to C₅ hydrocarbon, O, or S; Y is a bond, —C═O,—C═S, —C═N—NH₂, —C═N—OH, —CH—OH, —C═CH—CN, C═N—CN, —CH═CH—, —C═C(CH₃)₂,—C═N—OMe, —(C═O)—NH, —NH—(C═O), —(C═O)—O, —O—(C═O), —(CH₂)₁₋₅—(C═O),(C═O)—(CH₂)₁₋₅, —(SO₂)—, SO₂, SO or S; wherein said A and B rings areoptionally substituted by 1-5 substituents which are independentlyO-alkyl, O-haloalkyl, F, Cl, Br, I, CF₃, CN, —CH₂CN, NH₂, hydroxyl,—(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph,—NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂; i is aninteger between 0-5; l is an integer between 1-2; m is an integerbetween 1-3; and wherein if B is a benzene ring, a thiophene ring, afuran ring or an indole ring then X is not a bond or CH₂ and A is notindole; if B is indole then X is not O; and if B is a thiazole ring thenX is not a bond.
 2. The compound of claim 1, wherein said B ring is athiazole or an imidazole.
 3. (canceled)
 4. The compound of claim 1,wherein said A ring is a substituted aryl.
 5. The compound of claim 1,wherein said compound is represented by the structure of formula (II):

wherein B is

R₁, R₂, R₃, R₄, R₅ and R₆ are independently hydrogen, O-alkyl,O-haloalkyl, F, Cl, Br, I, CF₃, CN, —CH₂CN, NH₂, hydroxyl,—(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph,—NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂; R₁₀ andR₁₁ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, CF₃,CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂,—(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branched alkyl, haloalkyl,alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph,C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂; X is a bond, NH, C₁ to C₅hydrocarbon, O, or S; Y is a bond, —C═O, —C═S, —C═N—NH₂, —C═N—OH,—CH—OH, —C═CH—CN, —C═N—CN, —CH═CH—, C═CH(CH₃)₂, —C═N—OMe, —(C═O)—NH,—NH—(C═O), —(C═O)—O, —O—(C═O), —(CH₂)₁₋₅—(C═O), (C═O)—(CH₂)₁₋₅,—(SO₂)—NH—, —NH—(SO₂)—, SO₂, SO or S; i is an integer between 0-5; l isan integer between 1-2; n is an integer between 1-3; and m is an integerbetween 1-3; wherein if B is indole then X is not O; and if B is athiazole ring then X is not a bond.
 6. The compound of claim 5, whereinsaid B ring is a thiazole or an imidazole.
 7. (canceled)
 8. The compoundof claim 5, wherein said compound is represented by the structure offormula V:

B is

R₄, R₅ and R₆ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl,Br, I, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂,—(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branched alkyl, haloalkyl,alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph,C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂; R₁₀ and R₁₁ are independentlyhydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, CF₃, CN, —CH₂CN, NH₂,hydroxyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃,C₁-C₅ linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl,—OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ orNO₂; i is an integer between 0-5; l is an integer between 1-2; and n isan integer between 1-3.
 9. The compound of claim 8, wherein said B ringis an imidazole.
 10. The compound of claim 1, wherein said compound isrepresented by the structure of formula XI:

wherein X is a bond, NH or S; Q is O, NH or S; and A is substituted orunsubstituted single-, fused- or multiple-ring, aryl or (hetero)cyclicring systems; substituted or unsubstituted, saturated or unsaturatedN-heterocycles; substituted or unsubstituted, saturated or unsaturatedS-heterocycles; substituted or unsubstituted, saturated or unsaturatedO-heterocycles; substituted or unsubstituted, saturated or unsaturatedcyclic hydrocarbons; or substituted or unsubstituted or saturated orunsaturated mixed heterocycles; wherein said A ring is optionallysubstituted by 1-5 substituents which are independently O-alkyl,O-haloalkyl, F, Cl, Br, I, CF₃, CN, —CH₂CN, NH₂, hydroxyl,—(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph,—NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂; and iis an integer between 0-5; wherein if Q is S, then X is not a bond. 11.The compound of claim 10, wherein said compound is represented by thestructure of formula VIII:

R₄, R₅ and R₆ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl,Br, I, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂,—(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branched alkyl, haloalkyl,alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph,C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂; Q is S, O or NH; i is an integerbetween 0-5; and n is an integer between 1-3.
 12. The compound of claim10, wherein said compound is represented by the structure of formulaXI(b):

wherein R₄ and R₅ are independently hydrogen, O-alkyl, O-haloalkyl, F,Cl, Br, I, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂; i is an integer from 0-5;and n is an integer between 1-4.
 13. The compound of claim 10, whereinsaid compound is represented by the structure of formula XI(c):

wherein R₄ and R₅ are independently hydrogen, O-alkyl, O-haloalkyl, F,Cl, Br, I, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂; i is an integer from 0-5;and n is an integer between 1-4.
 14. The compound of claim 10, whereinsaid compound is represented by the structure of formula XI(e):

wherein R₄ and R₅ are independently hydrogen, O-alkyl, O haloalkyl, F,Cl, Br, I, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂; i is an integer from 0-5;and n is an integer between 1-4.
 15. The compound of claim 13, whereinsaid compound is compound 55, represented by the structure:


16. The compound of claim 14, wherein said compound is compound 17ya,represented by the structure:


17. The compound of claim 5, wherein said compound is represented by thestructure of formula (XVI):

wherein R₄ and R₅ are independently H, O-alkyl, I, Br, Cl, F, alkyl,haloalkyl, aminoalkyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂,—(CH₂)_(i)N(CH₃)₂, OCH₂Ph, OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkylor C(O)H; R₃ is I, Br, Cl, F; i is an integer between 0-5; and n is aninteger between 1-4.
 18. The compound of claim 17, wherein said R₃is For Cl.
 19. (canceled)
 20. The compound of claim 17, wherein said R₄ isCl or OCH₃.
 21. (canceled)
 22. The compound of claim 17, wherein said R₅is hydrogen.
 23. The compound of claim 10, wherein said compound is(2-(4-chlorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12fa):

(2-(4-chlorophenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone (12fb):

or (4-fluorophenyl)(2-(4-methoxyphenyl)-1H-imidazol-4-yl)methanone(12cb):


24. (canceled)
 25. (canceled)
 26. The compound according to claim 1 orits isomer, pharmaceutically acceptable salt, pharmaceutical product,tautomer, hydrate, N-oxide, or combinations thereof.
 27. Apharmaceutical composition comprising a compound according to claim 26and a pharmaceutically acceptable carrier.
 28. A method of treating,suppressing, reducing the severity, reducing the risk, inhibiting cancercomprising administering a compound according to claim 26 to a subjecthaving cancer under conditions effective to treat the cancer.
 29. Themethod of claim 28, wherein said cancer is selected from the groupconsisting of prostate cancer, breast cancer, ovarian cancer, skincancer, melanoma, lung cancer, colon cancer, leukemia, renal cancer, CNScancer, and combinations thereof.
 30. The method of claim 28, whereinsaid cancer is melanoma cancer metastatic melanoma, prostate cancer orovarian cancer.
 31. (canceled)
 32. (canceled)
 33. (canceled)
 34. Themethod of claim 28, wherein said administering is carried out incombination with another cancer therapy.
 35. A method of treating a drugresistant tumor or tumors comprising administering a compound accordingto claim 26 to a subject suffering from cancer under conditionseffective to treat the drug resistant tumor or tumors.
 36. The method ofclaim 35, wherein said tumor is melanoma cancer tumor, metastaticmelanoma tumor, prostate cancer tumor or ovarian cancer tumor 37.(canceled)
 38. (canceled)
 39. (canceled)
 40. The method according to 35,wherein said administering is carried out in combination with anothercancer therapy.
 41. (canceled)
 42. A compound represented by thestructure of formula IX:

R₄ and R₅ are independently selected from hydrogen, O-alkyl,O-haloalkyl, F, Cl, Br, I, CF₃, CN, —CH₂CN, NH₂, hydroxyl,—(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph,—NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —(O)NH₂ or NO₂; A′ issubstituted or unsubstituted single-, fused- or multiple-ring, aryl or(hetero)cyclic ring systems, including saturated and unsaturatedN-heterocycles, saturated and unsaturated S-heterocycles, and saturatedand unsaturated O-heterocycles, saturated or unsaturated cyclichydrocarbons, saturated or unsaturated mixed heterocycles or aliphaticstraight- or branched-chain C₁ to C₃₀ hydrocarbons; wherein said A′ ringis optionally substituted by 1-5 substituents which are independentlyO-alkyl, O-haloalkyl, F, Cl, Br, CF₃, CN, —CH₂CN, NH₂, hydroxyl,—(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph,—NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂; i is aninteger from 0-5; and n is an integer between 1-3.
 43. The compound ofclaim 42, wherein said A′ is substituted or unsubstituted phenyl, orsubstituted or unsubstituted indole.
 44. (canceled)
 45. The compound ofclaim 42, wherein said compound is represented by the structure offormula 6a:

formula 6b:

or formula 6c:


46. (canceled)
 47. (canceled)
 48. The compound according to claim 42 orits isomer, pharmaceutically acceptable salt, pharmaceutical product,tautomer, hydrate, N-oxide, or combinations thereof.
 49. Apharmaceutical composition comprising a compound according to claim 48and a pharmaceutically acceptable carrier.
 50. A method of treating,suppressing, reducing the severity, reducing the risk, inhibiting cancercomprising administering a compound according to claim 48 to a subjecthaving cancer under conditions effective to treat the cancer, whereinsaid cancer is selected from the group consisting of prostate cancer,breast cancer, ovarian cancer, skin cancer, melanoma, lung cancer, coloncancer, leukemia, renal cancer, CNS cancer, and combinations thereof.51. (canceled)
 52. The method of claim 50, wherein said cancer ismelanoma cancer metastatic melanoma, prostate cancer or ovarian cancer.53. (canceled)
 54. (canceled)
 55. (canceled)
 56. The method of claim 50,wherein said administering is carried out in combination with anothercancer therapy.
 57. A method of treating a drug resistant tumor ortumors comprising administering a compound according to claim 48 to asubject suffering from cancer under conditions effective to treat thedrug resistant tumor or tumors, wherein said tumor is melanoma cancertumor, metastatic melanoma tumor, prostate cancer tumor or ovariancancer tumor.
 58. (canceled)
 59. (canceled)
 60. (canceled) 61.(canceled)
 62. The method according to 57, wherein said administering iscarried out in combination with another cancer therapy.
 63. (canceled)